Anti-inflammatory, anti-cancer, and anti-angiogenic compounds, pharmaceutical compositions, and methods of making and using thereof

ABSTRACT

Compounds of the general Formula A-D-Y are disclosed with activity towards treating diseases related to inflammation, cancer, neurodegenerative diseases, and cardiovascular diseases. Pharmaceutical compositions, methods of making, and methods of use thereof are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit to U.S. Provisional Patent ApplicationNo. 62/564,610, filed Sep. 28, 2017, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to compounds of Formula A-D-Y, andmethods of making and using such compounds as treatments for diseases ordisorders.

BACKGROUND OF THE INVENTION

The cancer burden is rising globally, exerting significant strain onpopulations and health systems at all income levels. In May 2017, worldgovernments made a commitment to further invest in cancer control as apublic health priority. Each year, tens of millions of people arediagnosed with cancer around the world, and more than half of thepatients eventually die from it. A major reason for the increasingburden of cancer is the lack of efficacious and safe drugs that addressthis pressing medical need.

A remarkable property of the cancer cells is to respond to chemotherapyby becoming resistant to it, often rapidly. Ovarian cancer is a case inpoint. Ovarian cancer is the leading cause of death in women withgynecological cancer, with over 125,000 deaths annually worldwide.Ovarian cancer often spreads within the peritoneum; its stage dictatesits treatment. Indeed, in 75% of patients the cancer is spread into theperitoneal cavity (stage III) or more distantly (stage IV) and istreated with surgery plus chemotherapy with platinum and a taxane. Theresponse rate is 80% but most of those who respond develop drugresistance (often within 6 months), and subsequent treatment with otheragents is rarely successful. The 5-year survival of ovarian cancerpatients stage III disease is 40% and with stage IV 20%. Rates ofsurvival have not changed in the last 20 years.

Diabetic retinopathy (DR) causes significant visual loss on a globalscale. The global prevalence of diabetes mellitus is predicted toincrease dramatically in the coming decades, from an estimated 382million in 2013 to 592 million by 2035. Patients with diabetes suffermany life-limiting and life-threatening complications, includingmacrovascular-related stroke, ischemic heart disease, and peripheralartery disease and/or microvascular-related retinopathy, neuropathy, andnephropathy. Diabetic retinopathy (DR) is the most common microvascularcomplication of diabetes. The control of DR is still suboptimal andtreatments injectable into the eye, as currently available, areexpensive, associated with complication and not optimally efficacious.DR represents another pressing medical need of global importance.

Inflammation, a key component of the immune system, functions in bothdefense and pathophysiological events to maintain the homeostasis oftissues, organs and individual cells. Inflammation can be classified aseither acute or chronic. Acute inflammation is a short-term processcharacterized by the classic signs of inflammation, i.e., swelling,redness, pain, heat, and loss of function, due to infiltration oftissues by plasma and leukocytes. It occurs as long as the injuriousstimulus is present and ceases once the stimulus has been removed.Chronic inflammation is a pathological condition characterized byconcurrent active inflammation, tissue destruction, and attempts atrepair. Chronically inflamed tissue is characterized by the infiltrationof mononuclear immune cells (monocytes, macrophages, lymphocytes, andplasma cells), tissue destruction, and attempts at healing, whichinclude angiogenesis and fibrosis. Without inflammation, wounds andinfections would not be able to heal and progressive destruction of thetissue would threaten the survival of the organism. Uncheckedinflammation, on the other hand, can lead to a host of diseases, such ashay fever, atherosclerosis and other cardiovascular diseases,neurodegenerative diseases such as Alzheimer's, cancer and rheumatoidarthritis. For these reasons, inflammation is tightly regulated by thebody. Nonsteroidal anti-inflammatory drugs (NSAIDS) are the most widelyused anti-inflammatory compounds, with aspirin, the prototypical NSAID,still being one of the oldest and most extensively used medication inthe world. NSAIDs can also prevent cancer, likely through pleiotropiceffects.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a compound of Formula A-D-Y,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In some embodiments, the invention relates to acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1.

TABLE 1

A¹

A²

A³

A⁴

A⁵

A⁶

A⁷

A⁸

A⁹

A¹⁰

A¹¹

A¹²

A¹³

A¹⁴

A¹⁵

A¹⁶

A¹⁷

A¹⁸

A¹⁹

A²⁰

A²¹

A²²

A²³

A²⁴

A²⁵

A²⁶

A²⁷

A²⁸

A²⁹

A³⁰

A³¹

A³²

A³³

A³⁴

A³⁵

A³⁶

A³⁷

A³⁸

A³⁹

A⁴⁰

In one embodiment, the invention relates to a compound of Formula A-D-Y,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein D is selected from the group consisting of D¹to D⁹ as defined in Table 2. In one embodiment, the invention relates toa compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1, and D isselected from the group consisting of D¹ to D⁹ as defined in Table 2.

TABLE 2  

D¹

D²

D³

D⁴

D⁵

D⁶

D⁷

D⁸

D⁹ n is an integer between 0 and 12

In one embodiment, the invention relates to a compound of Formula A-D-Y,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein Y is selected from the group consisting of Y¹to Y⁷ as defined in Table 3. In one embodiment, the invention relates toa compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1, and Y isselected from the group consisting of Y¹ to Y⁷ as defined in Table 3. Inone embodiment, the invention relates to a compound of Formula A-D-Y, ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein D is selected from the group consisting of D¹to D⁹ as defined in Table 2, and Y is selected from the group consistingof Y¹ to Y⁷ as defined in Table 3. In one embodiment, the inventionrelates to a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A isselected from the group consisting of A¹ to A⁴⁰ as defined in Table 1, Dis selected from the group consisting of D¹ to D⁹ as defined in Table 2,and Y is selected from the group consisting of Y¹ to Y⁷ as defined inTable 3.

TABLE 3  

Y¹

Y²

Y³

Y⁴

Y⁵

Y⁶

Y⁷ m is an integer between 1 and 12

In some embodiments, the invention relates to a compound of FormulaA-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, wherein the compound hasanti-inflammatory, anticancer, or antiangiogenic effects.

In some embodiments, the invention relates to a pharmaceuticalcomposition including a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, A is selected from the group consisting of A¹ to A⁴⁰as defined in Table 1. In some embodiments, D is selected from the groupconsisting of D¹ to D⁹ as defined in Table 2. In some embodiments, Y isselected from the group consisting of Y¹ to Y⁷ as defined in Table 3.

In one embodiment, the invention relates to compound 1, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 1, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 2, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 2, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 3, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 3, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 4, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 4, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 5, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 5, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 6, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 6, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 7, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 7, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, Ais selected from the group consisting of A¹ to A⁴⁰ as defined inTable 1. In some embodiments, D is selected from the group consisting ofD¹ to D⁹ as defined in Table 2. In some embodiments, Y is selected fromthe group consisting of Y¹ to Y⁷ as defined in Table 3. In someembodiments, the compound, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, is included in apharmaceutical composition further including a pharmaceuticallyacceptable excipient. In some embodiments, the disease or disorder is aninflammation disease or disorder, a cancer, a neurodegenerative diseasesor disorder, a cardiovascular disease or disorder, an ocular disease ordisorder, or an angiogenic disease or disorder. In some embodiments, thecancer is ovarian cancer, colon cancer, leukemia, gastric cancer, lungcancer, pancreatic cancer, or a cancer characterized by a K-Rasmutation. In some embodiments, the cancer is chemoresistant to othertherapeutic agents. In some embodiments, treatment includes inhibitingVEGF expression.

In some embodiments, the disease or disorder is an eye related diseaseor disorder. The eye consists of the eyeball and its adnexa, whichincludes the structures outside of the eyeball, such as the orbit, eyemuscles, eyelids, eyelashes, conjunctiva, and lacrimal apparatus. Theeye and its various structures may be affected by a number ofpathological conditions including various inflammatory, autoimmune, andmetabolic conditions. In some embodiments, the invention relates to amethod for treating various diseases, disorders, and/or conditions ofthe eye and its associated structures, i.e., ophthalmic diseases,disorders, or conditions. In some embodiments, the ophthalmic diseases,disorders, or conditions treated by the compounds, compositions, and/orkits of the invention may include dry eye disease and retinopathy. Insome embodiments, retinopathy may include the diseases of diabeticretinopathy, retinopathy of prematurity, and/or hypertensiveretinopathy. In certain embodiments, retinopathy may be diabeticretinopathy.

In a further aspect, the invention is directed to compounds of FormulaA-D-Y, and pharmaceutical compositions thereof, as described generallyherein, useful in the treatment of human and animal inflammation relateddiseases including but not limited to neoplasms and cancer,rheumatologic diseases such as rheumatoid arthritis and Sjögren'ssyndrome, cardiovascular diseases, such as coronary artery disease,peripheral vascular disease and hypertension, neurodegenerative diseasessuch as Alzheimer's disease and its variants or cerebrovasculardiseases, autoimmune diseases such as lupus erythematosus, and otherconditions characterized by chronic inflammation of organs such as thelung, chronic bronchitis or the sinuses, such as chronic sinusitis,cardiovascular diseases, for example, coronary artery disease,peripheral vascular disease and hypertension, various neoplastic andpre-neoplastic diseases, for example, benign prostatic hypertrophy,prostate cancer, colon adenomas and colon cancer, cancer of the lung,lymphomas and leukemias. Similarly useful compounds have been describedin U.S. Pat. No. 8,236,820, the contents of which are incorporated intheir entirety herein.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of a solubilizingagent, e.g., vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000succinate), a sugar alcohol, e.g., mannitol, an acid, e.g., boric acid,and a preservative, e.g., polyquaternium-1 (polyquad). In someembodiments, such formulations may be used to deliver a compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, to the retina following topicaladministration to the eye. In some embodiments, such formulations may beused to deliver a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, to theretina in an amount sufficient to treat a retinopathy (i.e., atherapeutically effective amount).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about0.5% to about 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 0% toabout 25% vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000succinate), about 0% to about 10% mannitol, about 0% to about 10% boricacid, and about 0% to about 1% polyquaternium-1 (polyquad).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, greaterthan 0.5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of greater than 5%vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate),greater than 0.5% mannitol, greater than 0.5% boric acid, and greaterthan 0.001% polyquaternium-1 (polyquad).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, lessthan 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of less than 25%vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), lessthan 10% mannitol, less than 10% boric acid, and less than 1%polyquaternium-1 (polyquad).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about3.5% of a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 16%vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate),about 3.18% mannitol, about 1.2% boric acid, and about 0.005%polyquaternium-1 (polyquad).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of a gellingexcipient, e.g., gellan gum or sodium alginate, a poloxamer, asolubilizing agent, e.g., vitamin E TPGS, and a cyclodextrin (e.g.,(2-hydroxypropyl)-β-cyclodextrin). In some embodiments, suchformulations may allow for delivery of a compound of Formula A-D-Y, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, to anterior segments of the eye following topicaladministration.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of gellan gum,vitamin E TPGS, and a (2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about0.5% to about 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 0% toabout 5% gellan gum, about 0% to about 20% vitamin E TPGS, and about 0%to about 20% (2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, greaterthan 0.5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of greater than0.1% gellan gum, greater than 1% vitamin E TPGS, and greater than 5%(2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, lessthan 20% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of less than 5%gellan gum, less than 20% vitamin E TPGS, less than 20%(2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about2.4% to about 3% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 0.5%gellan gum, about 5% vitamin E TPGS, about 10%(2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about2.4% to about 3% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 0.4%gellan gum, about 10% vitamin E TPGS, about 5%(2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of sodium alginate,vitamin E TPGS, a (2-hydroxypropyl)-β-cyclodextrin, Tween, e.g., Tween80, poly(ethylene glycol) (PEG), e.g., PEG 400, and polyoxyl stearate.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about0.5% to about 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 0% toabout 5% sodium alginate, about 0% to about 20% vitamin E TPGS, andabout 0% to about 20% (2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, greaterthan 0.5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of greater than0.1% sodium alginate, greater than 1% vitamin E TPGS, and greater than5% (2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, lessthan 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of less than 5%sodium alginate, less than 20% vitamin E TPGS, less than 20%(2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 3%of a compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceuticallyacceptable carrier, and one or more of about 1.5% sodium alginate, about5% vitamin E TPGS, about 10% (2-hydroxypropyl)-β-cyclodextrin.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about0.5% to about 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 0% toabout 5% sodium alginate, about 0% to about 25% Tween 80, about 0% toabout 20% (2-hydroxypropyl)-β-cyclodextrin, about 0% to about 20% PEG400, and about 0% to about 10% polyoxyl stearate.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, greaterthan 0.5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of greater than 1%sodium alginate, greater than 1% Tween 80, greater than 1%(2-hydroxypropyl)-β-cyclodextrin, greater than 1% PEG 400, and greaterthan 1% polyoxyl stearate.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, lessthan 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of less than 5%sodium alginate, less than 25% Tween 80, less than 20%(2-hydroxypropyl)-β-cyclodextrin, less than 20% PEG 400, and less than10% polyoxyl stearate.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 3%of a compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceuticallyacceptable carrier, and one or more of about 1.5% sodium alginate, about15% Tween 80, about 10% (2-hydroxypropyl)-β-cyclodextrin, about 10% PEG400, and about 5% polyoxyl stearate.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 1%to about 5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 50% toabout 90% (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), about 0.05% toabout 1% cremophor EL (F1), and about 0.5% to about 5% Tween 80 (F2).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 1%to about 5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 50% toabout 90% (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), and about 0.05% toabout 1% cremophor EL (F1).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 1%to about 5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 50% toabout 90% (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), and about 0.5% toabout 5% Tween 80 (F2).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 3%to about 4% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 80%(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), and about 0.1% cremophor EL(F1).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 3%to about 4% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 80%(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), and about 1% Tween 80 (F2).

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about 1%to about 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 1% toabout 40% Poloxamer 407 and about 1% to about 20% vitamin E TPGS.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, greaterthan 1% of a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of greater than 1%Poloxamer 407 and greater than 1% vitamin E TPGS.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, lessthan 10% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of less than 40%Poloxamer 407 and less than 20% vitamin E TPGS.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising, by weight, about5.4% of a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, apharmaceutically acceptable carrier, and one or more of about 20%Poloxamer 407, and about 12% vitamin E TPGS.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a nanoparticleformulation comprising a compound of Formula A-D-Y, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, and a pharmaceutically acceptable carrier. In someembodiments, the nanoparticle formulation may include poly(ethyleneglycol) (PEG) nanoparticles. In some embodiments, the nanoparticleformulation may include methoxy poly(ethylene glycol)-poly(lactide)(mPEG-PLA) nanoparticles. In some embodiments, such formulations mayallow for delivery of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, toanterior segments of the eye following topical administration.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a nanoparticleformulation comprising, by weight, about 1% to about 5% of a compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier,and about 90% to about 98% mPEG-PLA.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a nanoparticleformulation comprising, by weight, about 3% to about 3.5% of a compoundof Formula A-D-Y, or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptablecarrier, and about 96.5% to about 97% mPEG-PLA.

In some embodiments, the compounds of Formula A-D-Y, or pharmaceuticallyacceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof,are analgesic agents.

In some embodiments, the compounds of Formula A-D-Y, or pharmaceuticallyacceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof,are anti-inflammatory agents.

In some embodiments, the compounds of Formula A-D-Y, or pharmaceuticallyacceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof,have a reduced risk of corneal melt or do not result in corneal meltupon administration to the eye.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofembodiments of the invention, will be better understood when read inconjunction with the appended drawings and figures.

FIG. 1 illustrates the ¹HNMR spectra of compound 1 salt.

FIG. 2 illustrates the MS of compound 1 salt.

FIG. 3 illustrates the ¹HNMR spectra of compound 2 salt.

FIG. 4 illustrates the MS of compound 2 salt.

FIG. 5 illustrates the ¹HNMR spectra of compound 5 salt.

FIG. 6 illustrates the MS of compound 5 salt.

FIG. 7 illustrates the ¹HNMR spectra of compound 6.

FIG. 8 illustrates the MS of compound 6.

FIG. 9 illustrates images and tumor growth curves in animals treatedwith compound 5 vs. control animals. Luciferase expressing SKOV-3 cellswere implanted into the peritoneal cavity of nude mice and treated withcompound 5 or vehicle. Compound 5 suppresses the growth ofintraperitoneal SKOV-3 tumors.

FIG. 10 illustrates tumor growth curves in animals treated with compound5 vs. control animals. A2780 and HEY are chemotherapy sensitive tumors,while the A2780cis are resistant to cisplatin, A2780ADR are resistant todoxorubicin (Adriamycin) and HWY-T30 are resistant to paclitaxel.Compound 5 inhibited tumor growth in both chemotherapy sensitive andresistant tumors, in contrast to the conventional chemotherapeuticagents. Values: mean±SD.

FIG. 11 illustrates the mechanism of the anti-ovarian cancer effect ofcompound 5. The main signaling pathways modulated by compound 5 areshown. Pointed arrows (→) indicate stimulation; T-shaped arrows indicateinhibition (AKT: Ak strain transforming; also known as Protein Kinase B;ATF4: Activating transcription factor 4; ATF6: Activating transcriptionfactor 6; CHOP: CCAAT-enhancer-binding protein (C/EBP) homologousprotein; COT: Cancer osaka thyroid; ERK: Extracellular signal-regulatedkinases; ERS: Endoplasmic reticulum stress response; GAPDH:Glyceraldehyde 3-phosphate dehydrogenase; GCN2: General controlnonderepressible 2; IRE1α: Inositol-requiring enzyme 1α; ISR: Integratedstress response; JNK: c-Jun N-terminal kinase; mTOR: The mammaliantarget of rapamycin; MAPK: Mitogen-activated protein kinases; MEK:Mitogen-activated protein kinase kinase; p-eIF2α: phospho-Eukaryotictranslation initiation factor 2A; PERK: Protein kinase RNA (PKR)-likeendoplasmic reticulum kinase; PI3K: Phosphatidylinositol 3 kinase; Raf:Rapidly accelerated fibrosarcoma; Ras: Retrovirus-associated DNAsequences; STAT3: Signal transducer and activator of transcription 3;XBP1: X-box binding protein).

FIGS. 12A-12C and FIGS. 13A-13C illustrate key findings related to themechanism of action of compound 5 against ovarian cancer. The studiesshown here were performed in SKOV-3 human ovarian cancer cells. FIG.12A: Left: Compound 5 increases the percentage of cells with acridineorange staining determined by flow cytometry (4%-38% after treatmentwith compound 5) and indicating the induction of autophagy. Right:Electron micrographs show morphological features of cells undergoingautophagy. Yellow arrowheads: vacuoles; white arrowheads:autophagosomes. FIG. 12B: Transmission electron microscopy establishesthe induction of endoplasmic reticulum (ER) stress by compound 5. N:nucleus; ER: endoplasmic reticulum with visible ribosomes. The leftmicrograph shown normal ER (circled) in a vehicle-treated cell. Theright one shows greatly dilated ER lumen (arrows) in a cell treated withcompound 5 1.5×IC₅₀. The latter finding is diagnostic of ER stress.Magnification: 6,800×. FIG. 12C: Compound 5 suppresses STAT3, mTOR andJNK activation by phosphorylation, as well as the levels of COT.

FIG. 13A: Compound 5 induces the phosphorylation of eIF2α, confirmingintegrated stress response. p-eIF2α induces ATF4 that suppresses 5′-capdependent translation initiation, shown below. FIG. 13B: Compound 5suppresses predominantly 5′-cap dependent translation initiation. Thelevels of reporter proteins used in the translation assay (Pierce™Renilla-Firefly Luciferase Dual Assay Kit; Thermo Scientific, GrandIsland, N.Y.) were normalized to the levels of intracellular FLUC-RLUCtranscripts and are shown as percent of untreated control cells.RLU=Relative light units. 5′-cap dependent translation initiation wasmuch less and occurred later. Values: Mean±SEM; *, p<0.05 and **, p<0.01vs. control. FIG. 13C: Compound 5 1.5×IC₅₀ activated by phosphorylationPERK and GCN2. Loading controls: β-actin and GADPH.

FIG. 14 illustrates key mechanistic steps in the induction of oxidativestress by compound 6 in SKOV-3 ovarian cancer cells and signalingthrough redox-sensitive pathways. (AKT: Ak strain transforming; alsoknown as Protein Kinase B; ASK1: apoptosis signal-regulating kinase 1;C6: compound 6; JNK: c-Jun N-terminal kinase; GAPDH: Glyceraldehyde3-phosphate dehydrogenase; GSH: glutathione; MAPK: mitogen-activatedprotein kinase; mTOR: the mammalian target of rapamycin; NADPH:nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factorkappa-light-chain-enhancer of activated B cells; p38: mitogen-activatedprotein kinase; Prx1: peroxiredoxin 1; Prx-SO₃: peroxiredoxin-sulfurtrioxide; ROS; reactive oxygen species; Trx1: thioredoxin 1; TrxR:thioredoxin reductase; TTFA: thenoyltrifluoroacetone).

FIGS. 15A-15F illustrate key findings related to the mechanism of actionof compound 6 against ovarian cancer. The studies shown here wereperformed in SKOV-3 human ovarian cancer cells. FIG. 15A: Stronginduction of mitochondrial superoxide anion detected with the MitoSoxRed molecular probe, using flow cytometry. TTFA, a mitochondrial ROSblocker, reversed the effect of compound 6 (C6). FIG. 15B. Compound 6suppressed the levels of GSH, the main cytosolic chemical antioxidant,in cells treated for 3 hours (*p<0.01). FIG. 15C. The levels of Prx-1and Prx-SO₃ in cells treated with compound 6 for 24 hours(immunoblotting). FIG. 15D. Compound 6 concentration-dependentlysuppressed the enzymatic activity of TrxR after 1 hour of treatment(*p<0.01). FIG. 15E. Protein lysates of cells treated with compound 6for 1 h with or without DTT 1 mM for 30 min and to immunoprecipitation(IP) immunoblotting (IB) as shown. Loading control: Trx-1.

FIG. 16A. Compound 6 suppressed the activation of NF-κB-DNA determinedby electrophoretic mobility shift assay in nuclear fractions of cells.To determine the specificity of the NF-κB transcription factor-DNAcomplex, the control nuclear fraction was incubated in the presence of100-fold molar excess of unlabeled oligonucleotide containing theconsensus sequence for either the specific (+NF-κB) or a non-specific(+AP-1) transcription factor. FIG. 16B. MAPK activation in response tocompound 6 was determined by immunoblotting cell lysates as indicated.FIG. 16C. AKT and mTOR activation by compound 6 was determined byimmunoblotting cell lysates as indicated.

FIG. 17 illustrates the synergistic effect between compound 5 andcyclophosphamide (CPA) in the inhibition of Taxol-resistant humanovarian cancer cell (HEY-T30) xenografts. Animals treated with either orboth compounds, responded similarly to compound 5 and CPA at the dosesused. Their combination produced tumor inhibition greater than the sumof each drug alone, i.e., synergistic inhibition.

FIG. 18 illustrates the effect of compounds 5 and 6 on K-Ras. FIG. 18A:Compound 6 suppressed of K-Ras activation. Cells with mutant K-Ras weretreated with compound 6 1.5×IC₅₀ for the respective time periods. K-Rasactivity was determined by Ras pull-down (Thermo Scientific; followingvendor instructions). K-Ras activation is suppressed 37% at 1 hr and 88%at 2 hrs compared to respective controls. FIG. 18B: Compound 5suppressed the palmitoylation of Ras in A2780 and A2780cis (resistant tocisplatin) ovarian cancer cells. Palmitoylation is detected by removingS-palmitate groups from proteins, creating new free thiols (where thepalmitic acid group used to be) and capturing the previouslyS-palmitoylated proteins on a resin, using a commercial kit (Badrilla,Leeds, UK). Ras was detected in the eluate by immunoblot.

FIG. 19 illustrates the normalization of retinal vasculature by compound6 in a model of oxygen-induced retinopathy in mice. FIG. 19A: Retinalflat mounts from C57Bl/6 mice at postnatal day 17 (P17) underoxygen-induced retinopathy conditions stained with isolectin B4 to labelthe vasculature. Vehicle treated mice (left) show the central avasculararea (blue arrow) and the peripheral neovascularization (red arrow).Compound 6 (right) normalized both. FIG. 19B: Quantification of theavascular and neovascular areas of the retina, expressed as percentageof the entire retina surface area.

FIG. 20 illustrates the effect of compound 6 on angiogenesis. Compound 6was applied at various concentrations to HUVEC human endothelial cellscultured appropriate extracellular matrix support, to formcapillary-like structures (a.k.a tubs). Images of chorioallantoicmembranes show that treatment with compound 6 (placed inside the spongeat the center of each image from which it was slowly released into thesurrounding tissues) markedly suppressed the formation of new vessels,whereas the main large vessels, already formed, remained unchanged.

FIG. 21 illustrates the normalization of retinal vasculature by compound2 in a mouse model of oxygen-induced retinopathy. FIG. 21A: Retinal flatmounts from C57Bl/6 mice at postnatal day 17 under oxygen-inducedretinopathy conditions stained with isolectin B4 to label thevasculature. Vehicle treated mice (left) show the central avascular area(blue arrow) and the peripheral neovascularization (red arrow). Compound2 (right) normalized both. FIG. 21B: Quantification of the avascular andneovascular areas of the retina, expressed as percentage of the entireretina surface area (n=8/group). Values are mean±SEM. Compared tovehicle, ***, p<0.0001; **, p<0.029

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art, which fallwithin the scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entireties.

Definitions

As used herein, the terms “administer,” “administration,” or“administering” refer to (1) providing, giving, dosing, and/orprescribing by either a health practitioner or his authorized agent orunder his or her direction according to the disclosure, and/or (2)putting into, taking, or consuming by a subject, for example a mammal,including a human, according to the disclosure.

The terms “co-administration,” “co-administering,” “administered incombination with,” “administering in combination with,” “simultaneous,”and “concurrent,” as used herein, encompass administration of two ormore active pharmaceutical ingredients to a subject so that both activepharmaceutical ingredients and/or their metabolites are present in thesubject at the same time. Co-administration includes simultaneousadministration in separate compositions, administration at differenttimes in separate compositions, or administration in a composition inwhich two or more active pharmaceutical ingredients are present. In someembodiments, simultaneous administration in separate compositions andadministration in a composition in which both agents are present arepreferred.

The terms “active pharmaceutical ingredient” and “drug” include thecompound of Formula A-D-Y, including, but not limited to, all examplesdescribed herein.

The term “isostere” refers to a group or molecule whose chemical and/orphysical properties are similar to those of another group or molecule. A“bioisostere” is a type of isostere and refers to a group or moleculewhose biological properties are similar to those of another group ormolecule. For example, for the compound of Formula A-D-Y describedherein, a carboxylic acid may be replaced by one of the followingbioisosteres for carboxylic acids, including, without limitation, alkylesters (COOR), acylsulfonamides (CONR—SO₂R), hydroxamic acids (CONR—OH),hydroxamates (CONR—OR), tetrazoles, hydroxyisoxazoles, isoxazol-3-ones,and sulfonamides (SO₂NR), where each R may independently representhydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. In vitro assays encompass cell-based assays in whichcells alive or dead are employed and may also encompass a cell-freeassay in which no intact cells are employed.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or combination of compounds as describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment. A therapeutically effectiveamount may vary depending upon the intended application (in vitro or invivo), or the subject and disease condition being treated (e.g., theweight, age and gender of the subject), the severity of the diseasecondition, the manner of administration, etc., which can readily bedetermined by one of ordinary skill in the art. The term also applies toa dose that will induce a particular response in target cells (e.g., thereduction of platelet adhesion and/or cell migration). The specific dosewill vary depending on the particular compounds chosen, the dosingregimen to be followed, whether the compound is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichthe compound is carried.

A “therapeutic effect” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. A prophylactic effectincludes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, preventing its recurrence, or any combination thereof.

As used herein, the terms “treat,” “treatment,” and/or “treating” mayrefer to the management of a disease, disorder, or pathologicalcondition, or symptom thereof with the intent to cure, ameliorate,stabilize, and/or control the disease, disorder, pathological conditionor symptom thereof. Regarding control of the disease, disorder, orpathological condition more specifically, “control” may include theabsence of condition progression, as assessed by the response to themethods recited herein, where such response may be complete (e.g.,placing the disease in remission) or partial (e.g., lessening orameliorating any symptoms associated with the condition). As usedherein, the terms “prevent,” “preventing,” and/or “prevention” may referto reducing the risk of developing a disease, disorder, or pathologicalcondition.

As used herein, the terms “modulate” and “modulation” refer to a changein biological activity for a biological molecule (e.g., a protein, gene,peptide, antibody, and the like), where such change may relate to anincrease in biological activity (e.g., increased activity, agonism,activation, expression, upregulation, and/or increased expression) ordecrease in biological activity (e.g., decreased activity, antagonism,suppression, deactivation, downregulation, and/or decreased expression)for the biological molecule. Without being limited by any particulartheory, the compounds described herein may, for example, modulate (i.e.,inhibit) VEGF expression, and/or K-Ras expression.

The terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or oncedaily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day,or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die,three times a day, or three times daily. The terms “QID,” “qid,” or“q.i.d.” mean quater in die, four times a day, or four times daily.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Preferred inorganic acids from whichsalts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.Preferred organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic, phosphoricacid, acid and salicylic acid. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins. Specific examples include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts. The term “cocrystal” refers to a molecular complexderived from a number of cocrystal formers known in the art. Unlike asalt, a cocrystal typically does not involve hydrogen transfer betweenthe cocrystal and the drug, and instead involves intermolecularinteractions, such as hydrogen bonding, aromatic ring stacking, ordispersive forces, between the cocrystal former and the drug in thecrystal structure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” or “physiologically compatible” carrier or carrier medium isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and inert ingredients. The use of such pharmaceuticallyacceptable carriers or pharmaceutically acceptable excipients for activepharmaceutical ingredients is well known in the art. Except insofar asany conventional pharmaceutically acceptable carrier or pharmaceuticallyacceptable excipient is incompatible with the active pharmaceuticalingredient, its use in the therapeutic compositions of the invention iscontemplated. Additional active pharmaceutical ingredients, such asother drugs, can also be incorporated into the described compositionsand methods.

A “prodrug” refers to a derivative of a compound described herein, thepharmacologic action of which results from the conversion by chemical ormetabolic processes in vivo to the active compound. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxyl orcarboxylic acid group of Formula A-D-Y. The amino acid residues includebut are not limited to the 20 naturally occurring amino acids commonlydesignated by one or three letter symbols but also include, for example,4-hydroxyproline, hydroxylysine, desmosine, isodesmosine,3-methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline,homocysteine, homoserine, ornithine and methionine sulfone. Additionaltypes of prodrugs are also encompassed. For instance, free carboxylgroups can be derivatized as amides or alkyl esters (e.g., methyl estersand acetoxy methyl esters). Prodrug esters as employed herein includesesters and carbonates formed by reacting one or more hydroxyls ofcompounds of the method of the invention with alkyl, alkoxy, or arylsubstituted acylating agents employing procedures known to those skilledin the art to generate acetates, pivalates, methylcarbonates, benzoatesand the like. As further examples, free hydroxyl groups may bederivatized using groups including but not limited to hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groupsare also included, as are carbonate prodrugs, sulfonate prodrugs,sulfonate esters and sulfate esters of hydroxyl groups. Free amines canalso be derivatized to amides, sulfonamides or phosphonamides. All ofthe stated prodrug moieties may incorporate groups including but notlimited to ether, amine and carboxylic acid functionalities. Moreover,any compound that can be converted in vivo to provide the bioactiveagent, e.g., a compound of Formula A-D-Y, is a prodrug within the scopeof the invention. Various forms of prodrugs are well known in the art. Acomprehensive description of pro drugs and prodrug derivatives aredescribed in: (a) The Practice of Medicinal Chemistry, Camille G.Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, editedby H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design andDevelopment, P. Krogsgaard-Larson and H. Bundgaard, eds., (HarwoodAcademic Publishers, 1991). In general, prodrugs may be designed toimprove the penetration of a drug across biological membranes in orderto obtain improved drug absorption, to prolong duration of action of adrug (slow release of the parent drug from a prodrug, decreasedfirst-pass metabolism of the drug), to target the drug action (e.g.,organ or tumor-targeting, lymphocyte targeting), to modify or improveaqueous solubility of a drug (e.g., i.v. preparations and eyedrops), toimprove topical drug delivery (e.g., dermal and ocular drug delivery),to improve the chemical/enzymatic stability of a drug, or to decreaseoff-target drug effects, and more generally in order to improve thetherapeutic efficacy of the compounds utilized in the invention.

Unless otherwise stated, the chemical structures depicted herein areintended to include compounds which differ only in the presence of oneor more isotopically enriched atoms. For example, compounds where one ormore hydrogen atoms is replaced by deuterium or tritium, or wherein oneor more carbon atoms is replaced by ¹³C-enriched or ¹⁴C-enrichedcarbons, are within the scope of this invention.

When ranges are used herein to describe, for example, physical orchemical properties such as molecular weight or chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. Use of the term “about” whenreferring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimentalvariability (or within statistical experimental error), and thus thenumber or numerical range may vary. The variation is typically from 0%to 15%, from 0% to 10%, from 0% to 5%, or the like, of the stated numberor numerical range.

As used herein, the term “about” means that amounts, sizes,formulations, parameters, shapes and other quantities andcharacteristics are not, and need not be exact, but may be approximateand/or larger or smaller, as desired, reflecting tolerances, conversionfactors, rounding off, measurement error and the like, and other factorsknown to those of skill in the art. In general, an amount, size,formulation, parameter, shape or other quantity or characteristic is“about” or “approximate” whether or not expressly stated to be such.

The transitional terms “comprising”, “consisting essentially of” and“consisting of”, when used in the appended claims, in original andamended form, define the claim scope with respect to what unrecitedadditional claim elements or steps, if any, are excluded from the scopeof the claim(s). The term “comprising” is intended to be inclusive oropen-ended and does not exclude any additional, unrecited element,method, step or material. The term “consisting of” excludes any element,step or material other than those specified in the claim and, in thelatter instance, impurities ordinary associated with the specifiedmaterial(s). The term “consisting essentially of” limits the scope of aclaim to the specified elements, steps or material(s) and those that donot materially affect the basic and novel characteristic(s) of theclaimed invention. All compounds, compositions, formulations, andmethods described herein that embody the present invention can, inalternate embodiments, be more specifically defined by any of thetransitional terms “comprising,” “consisting essentially of,” and“consisting of” The term “comprising” (and related terms such as“comprise” or “comprises” or “having” or “including”) includes thoseembodiments such as, for example, an embodiment of any composition ofmatter, method, or process that “consist of” or “consist essentially of”the described features.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., (C₁₋₁₀)alkyl orC₁₋₁₀ alkyl). Whenever it appears herein, a numerical range such as “1to 10” refers to each integer in the given range, e.g., “1 to 10 carbonatoms” means that the alkyl group may consist of 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms,although the definition is also intended to cover the occurrence of theterm “alkyl” where no numerical range is specifically designated.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl,tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl,nonyl and decyl. The alkyl moiety may be attached to the rest of themolecule by a single bond, such as for example, methyl (Me), ethyl (Et),n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of substituents which are independentlyheteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂ where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively.

“Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Alkylheterocycloalkyl” refers to an -(alkyl) heterocyclic radical wherealkyl and heterocycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heterocycloalkyl and alkyl respectively.

An “alkene” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon double bond, and an “alkyne” moietyrefers to a group consisting of at least two carbon atoms and at leastone carbon-carbon triple bond. The alkyl moiety, whether saturated orunsaturated, may be branched, straight chain, or cyclic.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,(C₂₋₁₀alkenyl or C₂₋₁₀ alkenyl). Whenever it appears herein, a numericalrange such as “2 to 10” refers to each integer in the given range—e.g.,“2 to 10 carbon atoms” means that the alkenyl group may consist of 2carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.The alkenyl moiety may be attached to the rest of the molecule by asingle bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl(i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical wherealkenyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkenyl and cycloalkyl respectively.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e.,(C₂₋₁₀alkynyl or C₂₋₁₀ alkynyl). Whenever it appears herein, a numericalrange such as “2 to 10” refers to each integer in the given range—e.g.,“2 to 10 carbon atoms” means that the alkynyl group may consist of 2carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.The alkynyl may be attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.Unless stated otherwise specifically in the specification, an alkynylgroup is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, acylsulfonamido, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical wherealkynyl and cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkynyl and cycloalkyl respectively.

“Acylsulfonamide” refers to the group —C(═O)NR^(a)—S(═O)R^(a), whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carbonyl” refers to the group —C(═O)—. Carbonyl groups may besubstituted with the following exemplary substituents: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,hydroxamate, acylsulfonamido, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —NR^(a)—OR^(a)—, —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (i.e., (C₃₋₁₀)cycloalkyl or C₃₋₁₀ cycloalkyl). Whenever it appearsherein, a numerical range such as “3 to 10” refers to each integer inthe given range—e.g., “3 to 10 carbon atoms” means that the cycloalkylgroup may consist of 3 carbon atoms, etc., up to and including 10 carbonatoms. Illustrative examples of cycloalkyl groups include, but are notlimited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwisespecifically in the specification, a cycloalkyl group is optionallysubstituted by one or more substituents which independently are: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —S(O)_(t)R^(a)— (where t is 1 or2), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical wherecycloalkyl and alkenyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkenyl, respectively.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for cycloalkyl and heterocycloalkyl,respectively.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for cycloalkyl and heteroaryl, respectively.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 8carbon atoms of a straight, branched, cyclic configuration andcombinations thereof attached to the parent structure through an oxygen.Examples include, but are not limited to, methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers toalkoxy groups containing one to six carbons.

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)). Unless statedotherwise specifically in the specification, the alkyl moiety of analkoxy group is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, acylsulfonamido,alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a(C1-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbonatoms attached through its oxygen to a carbonyl linker. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxygroup is a lower alkoxy group.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality. Unless stated otherwise specificallyin the specification, the alkyl moiety of an alkoxycarbonyl group isoptionally substituted by one or more substituents which independentlyare: alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyl” refers to the groups (alkyl)-C(O)—, (aryl)-C(O)—,(heteroaryl)-C(O)—, (heteroalkyl)-C(O)— and (heterocycloalkyl)-C(O)—,wherein the group is attached to the parent structure through thecarbonyl functionality. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise specifically inthe specification, the alkyl, aryl or heteroaryl moiety of the acylgroup is optionally substituted by one or more substituents which areindependently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Acyloxy” refers to a R(C═O)O— radical wherein R is alkyl, aryl,heteroaryl, heteroalkyl or heterocycloalkyl, which are as describedherein. If the R radical is heteroaryl or heterocycloalkyl, the heteroring or chain atoms contribute to the total number of chain or ringatoms. Unless stated otherwise specifically in the specification, the Rof an acyloxy group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Amino” or “amine” refers to a —N(R^(a))₂ radical group, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless statedotherwise specifically in the specification. When a —N(R^(a))₂ group hastwo R^(a) substituents other than hydrogen, they can be combined withthe nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example,—N(R^(a))₂ is intended to include, but is not limited to, 1-pyrrolidinyland 4-morpholinyl. Unless stated otherwise specifically in thespecification, an amino group is optionally substituted by one or moresubstituents which independently are: alkyl, acylsulfonamido,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)NR^(a)R^(b) or —N R^(a)C(O)R^(b), where R^(a) and R^(b) are selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon), each of which moiety may itself be optionally substituted.The R^(a) and R^(b) of —C(O)N R^(a)R^(b) amide may optionally be takentogether with the nitrogen to which they are attached to form a 4-, 5-,6- or 7-membered ring. Unless stated otherwise specifically in thespecification, an amido group is optionally substituted independently byone or more of the substituents as described herein for alkyl, amino,cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be anamino acid or a peptide molecule attached to a compound disclosedherein, thereby forming a prodrug. The procedures and specific groups tomake such amides are known to those of skill in the art and can readilybe found in seminal sources such as Greene and Wuts, Protective Groupsin Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y.,1999, which is incorporated herein by reference in its entirety.

“Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six toten ring atoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at leastone ring having a conjugated pi electron system which is carbocyclic(e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed fromsubstituted benzene derivatives and having the free valences at ringatoms are named as substituted phenylene radicals. Bivalent radicalsderived from univalent polycyclic hydrocarbon radicals whose names endin “-yl” by removal of one hydrogen atom from the carbon atom with thefree valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange, e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Unless stated otherwisespecifically in the specification, an aryl moiety is optionallysubstituted by one or more substituents which are independently alkyl,heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively.

“Ester” refers to a chemical radical of formula —COOR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). The procedures and specific groups to makeesters are known to those of skill in the art and can readily be foundin seminal sources such as Greene and Wuts, Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference in its entirety. Unless statedotherwise specifically in the specification, an ester group isoptionally substituted by one or more substituents which independentlyare: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,trifluoromethoxy, nitro, trimethylsilanyl, —OR^(a), —SR^(a),—S(O)_(t)R^(a)— (where t is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or PO₃(R^(a))₂, where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Halo,” “halide,” or, alternatively, “halogen” is intended to meanfluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

“Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionallysubstituted alkyl, alkenyl and alkynyl radicals and which have one ormore skeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given—e.g., C₁-C₄ heteroalkyl which refers to thechain length in total, which in this example is 4 atoms long. Aheteroalkyl group may be substituted with one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl,acylsulfonamido, cycloalkyl, heterocycloalkyl, hydroxamate, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —S(O)_(t)R^(a)— (wheret is 1 or 2), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl, respectively.

“Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl, respectively.

“Heteroalkylheterocycloalkyl” refers to an-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl, respectively.

“Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl, respectively.

“Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to18-membered aromatic radical (e.g., C₅-C₁₃ heteroaryl) that includes oneor more ring heteroatoms selected from nitrogen, oxygen and sulfur, andwhich may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range—e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. Bivalent radicalsderived from univalent heteroaryl radicals whose names end in “-yl” byremoval of one hydrogen atom from the atom with the free valence arenamed by adding “-idene” to the name of the corresponding univalentradical—e.g., a pyridyl group with two points of attachment is apyridylidene. A N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. The polycyclic heteroaryl group may befused or non-fused. The heteroatom(s) in the heteroaryl radical areoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl,benzothiazolyl, benzothienyl(benzothiophenyl),benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl, isoxazol-3-one,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteroaryl moiety is optionally substituted by one or more substituentswhich are independently: alkyl, acylsulfonamido, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl,heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —S(O)_(t)R^(a)— (where t is 1 or 2),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O—) substituents, such as, for example, pyridinylN-oxides.

“Heteroarylalkyl” refers to a moiety having an aryl moiety, as describedherein, connected to an alkylene moiety, as described herein, whereinthe connection to the remainder of the molecule is through the alkylenegroup.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Whenever itappears herein, a numerical range such as “3 to 18” refers to eachinteger in the given range—e.g., “3 to 18 ring atoms” means that theheterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc.,up to and including 18 ring atoms. Unless stated otherwise specificallyin the specification, the heterocycloalkyl radical is a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fusedor bridged ring systems. The heteroatoms in the heterocycloalkyl radicalmay be optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heterocycloalkyl radical is partially orfully saturated. The heterocycloalkyl may be attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocycloalkyl moiety is optionally substituted byone or more substituents which independently are: alkyl,acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —S(O)_(t)R^(a)— (where t is 1 or 2),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently selected fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms, and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteroatoms independentlyselected from oxygen, sulfur, and nitrogen and is not aromatic.

“Hydroxamate” refers to the —C(O)NR^(a)OR^(a) moiety, where each R^(a)is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Isomers” are different compounds that have the same molecular formula.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space—i.e., having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate. “Diastereoisomers” are stereoisomers that have atleast two asymmetric atoms, but which are not mirror-images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either (R) or(S). Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that can be defined, interms of absolute stereochemistry, as (R) or (S). The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible isomers, including racemic mixtures, optically pureforms and intermediate mixtures. Optically active (R)- and (S)-isomerscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers.

“Enantiomeric purity” as used herein refers to the relative amounts,expressed as a percentage, of the presence of a specific enantiomerrelative to the other enantiomer. For example, if a compound, which maypotentially have an (R)- or an (S)-isomeric configuration, is present asa racemic mixture, the enantiomeric purity is about 50% with respect toeither the (R)- or (S)-isomer. If that compound has one isomeric formpredominant over the other, for example, 80% (S)-isomer and 20%(R)-isomer, the enantiomeric purity of the compound with respect to the(S)-isomeric form is 80%. The enantiomeric purity of a compound can bedetermined in a number of ways known in the art, including but notlimited to chromatography using a chiral support, polarimetricmeasurement of the rotation of polarized light, nuclear magneticresonance spectroscopy using chiral shift reagents which include but arenot limited to lanthanide containing chiral complexes or Pirkle'sreagents, or derivatization of a compounds using a chiral compound suchas Mosher's acid followed by chromatography or nuclear magneticresonance spectroscopy.

In some embodiments, the enantiomerically enriched composition has ahigher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts, or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions, Wiley Interscience, NewYork (1981); E. L. Eliel, Stereochemistry of Carbon Compounds,McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen,Stereochemistry of Organic Compounds, Wiley-Interscience, New York(1994).

The terms “enantiomerically enriched” and “non-racemic,” as used herein,refer to compositions in which the percent by weight of one enantiomeris greater than the amount of that one enantiomer in a control mixtureof the racemic composition (e.g., greater than 1:1 by weight). Forexample, an enantiomerically enriched preparation of the (S)-enantiomer,means a preparation of the compound having greater than 50% by weight ofthe (S)-enantiomer relative to the (R)-enantiomer, such as at least 75%by weight, or such as at least 80% by weight. In some embodiments, theenrichment can be significantly greater than 80% by weight, providing a“substantially enantiomerically enriched” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least 85% by weight of one enantiomer relative to otherenantiomer, such as at least 90% by weight, or such as at least 95% byweight. The terms “enantiomerically pure” or “substantiallyenantiomerically pure” refers to a composition that comprises at least98% of a single enantiomer and less than 2% of the opposite enantiomer.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. “Tautomerization” is a form of isomerization andincludes prototropic or proton-shift tautomerization, which isconsidered a subset of acid-base chemistry. “Prototropictautomerization” or “proton-shift tautomerization” involves themigration of a proton accompanied by changes in bond order, often theinterchange of a single bond with an adjacent double bond. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. An example of tautomerization is keto-enoltautomerization. A specific example of keto-enol tautomerization is theinterconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-onetautomers. Another example of tautomerization is phenol-ketotautomerization. A specific example of phenol-keto tautomerization isthe interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under selectedreaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Examples of such groups, unless otherwisespecified, include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxyand tosyloxy groups.

“Protecting group” is intended to mean a group that selectively blocksone or more reactive sites in a multifunctional compound such that achemical reaction can be carried out selectively on another unprotectedreactive site and the group can then be readily removed or deprotectedafter the selective reaction is complete. A variety of protecting groupsare disclosed, for example, in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons,New York (1999).

“Solvate” refers to a compound in physical association with one or moremolecules of a pharmaceutically acceptable solvent.

“Substituted” means that the referenced group may have attached one ormore additional groups, radicals or moieties individually andindependently selected from, for example, acyl, alkyl, alkylaryl,cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl,heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl,isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl,perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl,sulfoxyl, sulfonate, urea, and amino, including mono- and di-substitutedamino groups, and protected derivatives thereof. The substituentsthemselves may be substituted, for example, a cycloalkyl substituent mayitself have a halide substituent at one or more of its ring carbons. Theterm “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

“Sulfanyl” refers to groups that include —S-(optionally substitutedalkyl), —S-(optionally substituted aryl), —S-(optionally substitutedheteroaryl) and —S-(optionally substituted heterocycloalkyl).

“Sulfinyl” refers to groups that include —S(O)—H, —S(O)-(optionallysubstituted alkyl), —S(O)-(optionally substituted amino),—S(O)-(optionally substituted aryl), —S(O)-(optionally substitutedheteroaryl) and —S(O)-(optionally substituted heterocycloalkyl).

“Sulfonyl” refers to groups that include —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-(optionally substituted amino),—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), and —S(O₂)-(optionally substituted heterocycloalkyl).

“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)₂—NRR radical, whereeach R is selected independently from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). The R groups in —NRR ofthe —S(═O)₂—NRR radical may be taken together with the nitrogen to whichit is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamidogroup is optionally substituted by one or more of the substituentsdescribed for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon). Asulfonate group is optionally substituted on R by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroaryl,respectively.

Compounds of the invention also include crystalline and amorphous formsof those compounds, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof “Crystalline form” and“polymorph” are intended to include all crystalline and amorphous formsof the compound, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto.

Compounds of Formula A-D-Y

This invention provides novel compounds that have biological propertiesuseful for the treatment of any of a number of conditions or diseasesgenerally characterized by abnormal inflammation, or prophylaxis ininstances wherein a risk of appearance of such conditions or diseases ispresent.

In one embodiment, the invention relates to a compound of Formula A-D-Y,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In some embodiments, the invention relates to acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1.

TABLE 1

A¹

A²

A³

A⁴

A⁵

A⁶

A⁷

A⁸

A⁹

A¹⁰

A¹¹

A¹²

A¹³

A¹⁴

A¹⁵

A¹⁶

A¹⁷

A¹⁸

A¹⁹

A²⁰

A²¹

A²²

A²³

A²⁴

A²⁵

A²⁶

A²⁷

A²⁸

A²⁹

A³⁰

A³¹

A³²

A³³

A³⁴

A³⁵

A³⁶

A³⁷

A³⁸

A³⁹

A⁴⁰

In one embodiment, the invention relates to a compound of Formula A-D-Y,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein D is selected from the group consisting of D¹to D⁹ as defined in Table 2. In one embodiment, the invention relates toa compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1, and D isselected from the group consisting of D¹ to D⁹ as defined in Table 2.

TABLE 2  

D¹

D²

D³

D⁴

D⁵

D⁶

D⁷

D⁸

D⁹ n is an integer between 0 and 12

In one embodiment, the invention relates to a compound of Formula A-D-Y,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein Y is selected from the group consisting of Y¹to Y⁷ as defined in Table 3. In one embodiment, the invention relates toa compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1, and Y isselected from the group consisting of Y¹ to Y⁷ as defined in Table 3. Inone embodiment, the invention relates to a compound of Formula A-D-Y, ora pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, wherein D is selected from the group consisting of D¹to D⁹ as defined in Table 2, and Y is selected from the group consistingof Y¹ to Y⁷ as defined in Table 3. In one embodiment, the inventionrelates to a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A isselected from the group consisting of A¹ to A⁴⁰ as defined in Table 1, Dis selected from the group consisting of D¹ to D⁹ as defined in Table 2,and Y is selected from the group consisting of Y¹ to Y⁷ as defined inTable 3.

TABLE 3  

Y¹

Y²

Y³

Y⁴

Y⁵

Y⁶

Y⁷ m is an integer between 1 and 12

In some embodiments, the invention relates to a compound of FormulaA-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, wherein the compound hasanti-inflammatory, anticancer, or antiangiogenic effects.

In some embodiments, the invention relates to a pharmaceuticalcomposition including a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, A is selected from the group consisting of A¹ to A⁴⁰as defined in Table 1. In some embodiments, D is selected from the groupconsisting of D¹ to D⁹ as defined in Table 2. In some embodiments, Y isselected from the group consisting of Y¹ to Y⁷ as defined in Table 3.

In one embodiment, the invention relates to compound 1, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 1, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 2, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 2, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 3, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 3, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 4, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 4, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 5, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 5, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 6, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 6, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In one embodiment, the invention relates to compound 7, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In one embodiment, the invention relates to apharmaceutical composition including compound 7, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and apharmaceutically acceptable excipient.

In some embodiments, the invention relates to compounds 10 to 107 asdescribed in Table 4, or pharmaceutically acceptable salts, solvates,hydrates, cocrystals, or prodrugs thereof. In some embodiments, theinvention relates to pharmaceutical compositions including one or moreof compounds 10 to 107, or pharmaceutically acceptable salts, solvates,hydrates, cocrystals, or prodrugs thereof, and one or morepharmaceutically acceptable excipients.

TABLE 4 10 A19-D1-Y1 11 A19-D1-Y2 12 A19-D1-Y3 13 A19-D1-Y4 14 A19-D1-Y515 A19-D1-Y6 16 A19-D1-Y7 17 A19-D2-Y1 18 A19-D2-Y2 19 A19-D2-Y3 20A19-D2-Y4 21 A19-D2-Y5 22 A19-D2-Y6 23 A19-D2-Y7 24 A19-D3-Y1 25A19-D3-Y2 26 A19-D3-Y3 27 A19-D3-Y4 28 A19-D3-Y5 29 A19-D3-Y6 30A19-D3-Y7 31 A19-D4-Y1 32 A19-D4-Y2 33 A19-D4-Y3 34 A19-D4-Y4 35A19-D4-Y5 36 A19-D4-Y6 37 A19-D4-Y7 38 A19-D5-Y1 39 A19-D5-Y2 40A19-D5-Y3 41 A19-D5-Y4 42 A19-D5-Y5 43 A19-D5-Y6 44 A19-D5-Y7 45A19-D6-Y1 46 A19-D6-Y2 47 A19-D6-Y3 48 A19-D6-Y4 49 A19-D6-Y5 50A19-D6-Y6 51 A19-D6-Y7 52 A19-D7-Y1 53 A19-D7-Y2 54 A19-D7-Y3 55A19-D7-Y4 56 A19-D7-Y5 57 A19-D7-Y6 58 A19-D7-Y7 59 A30-D1-Y1 60A30-D1-Y2 61 A30-D1-Y3 62 A30-D1-Y4 63 A30-D1-Y5 64 A30-D1-Y6 65A30-D1-Y7 66 A30-D2-Y1 67 A30-D2-Y2 68 A30-D2-Y3 69 A30-D2-Y4 70A30-D2-Y5 71 A30-D2-Y6 72 A30-D2-Y7 73 A30-D3-Y1 74 A30-D3-Y2 75A30-D3-Y3 76 A30-D3-Y4 77 A30-D3-Y5 78 A30-D3-Y6 79 A30-D3-Y7 80A30-D4-Y1 81 A30-D4-Y2 82 A30-D4-Y3 83 A30-D4-Y4 84 A30-D4-Y5 85A30-D4-Y6 86 A30-D4-Y7 87 A30-D5-Y1 88 A30-D5-Y2 89 A30-D5-Y3 90A30-D5-Y4 91 A30-D5-Y5 92 A30-D5-Y6 93 A30-D5-Y7 94 A30-D6-Y1 95A30-D6-Y2 96 A30-D6-Y3 97 A30-D6-Y4 98 A30-D6-Y5 99 A30-D6-Y6 100A30-D6-Y7 101 A30-D7-Y1 102 A30-D7-Y2 103 A30-D7-Y3 104 A30-D7-Y4 105A30-D7-Y5 106 A30-D7-Y6 107 A30-D7-Y7

Methods of Treatment

The compounds and compositions described herein can be used in methodsfor treating diseases. In one embodiment, the invention relates to amethod of treating a disease or disorder in a patient in need thereof,including administering to the patient a therapeutically effectiveamount of a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof. In oneembodiment, the patient or subject is a mammal, such as a human. In anembodiment, the patient or subject is a human. In an embodiment, thepatient or subject is an animal, for example a farm animal, or acompanion animal. In an embodiment, the patient or subject is a canine,feline, or equine.

In some embodiments, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table 1.

In some embodiments, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein D is selectedfrom the group consisting of D¹ to D⁹ as defined in Table 2.

In some embodiments, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein Y is selectedfrom the group consisting of Y¹ to Y⁷ as defined in Table 3.

In some embodiments, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein the compound,or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, is included in a pharmaceutical composition furtherincluding a pharmaceutically acceptable excipient.

In some embodiments, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein the disease ordisorder is an inflammation disease or disorder, a cancer, aneurodegenerative diseases or disorder, a cardiovascular disease ordisorder, an ocular disease or disorder, or an angiogenic disease ordisorder.

In some embodiments, the invention relates to a method of treatingcancer in a patient in need thereof, including administering to thepatient a therapeutically effective amount of a compound of FormulaA-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, wherein the cancer is ovarian cancer,colon cancer, leukemia, gastric cancer, lung cancer, pancreatic cancer,or a cancer characterized by a K-Ras mutation.

In some embodiments, the invention relates to a method of treatingcancer in a patient in need thereof, including administering to thepatient a therapeutically effective amount of a compound of FormulaA-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, wherein the cancer is chemoresistant toother therapeutic agents.

In some embodiments, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein treatmentincludes inhibiting VEGF expression.

In some embodiments, the invention relates to a method of treatingdiabetic retinopathy in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof.

In some embodiments, the invention relates to a method of treatinginflammation in the eye in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof.

In some embodiments, the invention relates to a method of treating dryeye in a patient in need thereof, including administering to the patienta therapeutically effective amount of a compound of Formula A-D-Y, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.

In some embodiments, the invention relates to a method of treating adisease or disorder of the anterior of the eye in a patient in needthereof, including administering to the patient a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

In some embodiments, the invention relates to a method of treating adisease or disorder of the posterior of the eye in a patient in needthereof, including administering to the patient a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

In some embodiments, the compounds and compositions described herein canbe used in methods for treating diseases associated with the up- and/ordownregulation of VEGF expression, and/or K-Ras expression.

In one embodiment, the invention relates to a method of treating adisease alleviated by administering a compound of Formula A-D-Y in apatient in need thereof, including administering to the patient atherapeutically effective amount of a compound of Formula A-D-Y in adosage unit form. In one embodiment, the dosage unit comprises aphysiologically compatible carrier medium.

In one embodiment, the invention relates to a method of treating adisease alleviated by administering a compound of Formula A-D-Y to apatient in need thereof, including administering to the patient atherapeutically effective amount of a compound of Formula A-D-Y, whereinthe disease is cancer or an inflammatory disease. In some embodiments,the disease is rheumatoid arthritis, a cardiovascular disease, multiplesclerosis, inflammatory bowel disease, chronic obstructive pulmonarydisease (COPD), asthma, acute respiratory distress syndrome (ARDS), oracute lung injury (ALI). In one embodiment, the disease is ahyperproliferative diseases. In some embodiments, the hyperproliferativedisorder is cancer. In some embodiments, the cancer is pancreaticcancer, breast cancer, prostate cancer, lymphoma, skin cancer, coloncancer, melanoma, malignant melanoma, ovarian cancer, brain cancer,primary brain carcinoma, head-neck cancer, glioma, glioblastoma, livercancer, bladder cancer, non-small cell lung cancer, head or neckcarcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma,small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicularcarcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma,colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroidcarcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenalcarcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortexcarcinoma, malignant pancreatic insulinoma, malignant carcinoidcarcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia,cervical hyperplasia, leukemia, acute lymphocytic leukemia, chroniclymphocytic leukemia, acute myelogenous leukemia, chronic myelogenousleukemia, chronic granulocytic leukemia, acute granulocytic leukemia,hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma,polycythemia vera, essential thrombocytosis, Hodgkin's disease,non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primarymacroglobulinemia, or retinoblastoma, and the like. In otherembodiments, the cancer is acoustic neuroma, adenocarcinoma,angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma,bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma,cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectalcancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma,endotheliocarcinoma, ependymoma, epithelial carcinoma, esophagealcancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastomamultiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma,kidney cancer, leiomyosarcoma, liposarcoma, lung cancer,lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasalcancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma,papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectalcancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous glandcarcinoma, seminoma, skin cancer, squamous cell carcinoma, stomachcancer, sweat gland carcinoma, synovioma, testicular cancer, small celllung carcinoma, throat cancer, uterine cancer, Wilm's tumor, bloodcancer, acute erythroleukemic leukemia, acute lymphoblastic B-cellleukemia, acute lymphoblastic T-cell leukemia, acute lymphoblasticleukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia,acute myeloblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocytic leukemia, acute promyelocytic leukemia, acuteundifferentiated leukemia, chronic lymphocytic leukemia, chronicmyelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chaindisease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma,polycythemia vera, or Waldenstrom's macroglobulinemia.

In some embodiments, the hyperproliferative disorder (e.g., cancer)treated by the compounds and compositions described herein includescells having VEGF and/or K-Ras related protein expression.

In one embodiment, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and one or moreadditional therapeutic agents, including chemotherapeutic and/orimmunotherapeutic agents.

In one embodiment, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and one or moreadditional therapeutic agents, including an antibiotic. In someembodiments, the antibiotic may include one or more of tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,oxytetracycline, chloramphenicol, gentamycin, and erythromycin. Otherantibiotics include aminoglycoside, ampicillin, carbenicillin,cefazolin, cephalosporin, chloramphenicol, clindamycin, everninomycin,gentamycin, kanamycin, lipopeptides, methicillin, nafcillin, novobiocia,oxazolidinones, penicillin, quinolones, rifampin, streptogramins,streptomycin, sulfamethoxazole, sulfonamide, trimethoprim andvancomycin. In some embodiments, the compound of Formula A-D-Y does notinhibit, impede, or otherwise delay or prevent the efficacy of theantibiotic, for example a co-administered antibiotic. In someembodiments, the antibiotic does not inhibit, impede, or otherwise delayor prevent the efficacy of the compound of Formula A-D-Y, for example aco-administered compound of Formula A-D-Y.

In one embodiment, the invention relates to a method of treating adisease or disorder in a patient in need thereof, includingadministering to the patient a therapeutically effective amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and one or moreadditional therapeutic agents, including an antibiotic, includingtopical treatment of ocular inflammatory conditions. Inflammatoryconditions of the eye are frequent. Often when the eye is inflamed, itis clinically difficult to assess whether the inflammation is due to aninfectious agent, to non-infectious causes, or both. As the treatmentfor these two etiologies is different, in some embodiments, there is aneed for timely treatment because, if untreated, these diseases ordisorders can have catastrophic consequences for the eye. In someembodiments, the use of a combination drug with an anti-infectivecomponent is indicated where there is a risk of infection, and/orbacteria is potentially present in the eye. In some embodiments, aneffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, iscombined with one or more additional therapeutic agents in an eye dropformulation, or an ophthalmic ointment formulation. In some embodiments,the additional therapeutic agent is neomycin sulfate. In someembodiments, the additional therapeutic agent is polymyxin B sulfate. Insome embodiments, the additional therapeutic agent is ananti-inflammatory agent. In some embodiments, the additional therapeuticagent is dexamethasone. In some embodiments, the additional therapeuticagent is cortisone or other corticosteroid. In some embodiments, theadditional therapeutic agent is tobramycin. In some embodiments, aneffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, iscombined with one or more additional therapeutic agents in an eye dropformulation, or an ophthalmic ointment formulation, excludingdexamethasone.

The term “compound with reduced risk of corneal melt” refers tocompounds that are less likely to cause corneal melt in a patient beingtreated when compared to an NSAID known to cause corneal melt (e.g.,diclofenac (see, e.g., Julianne, C. et al. “Corneal Melting Associatedwith Use of Topical Nonsteroidal Anti-Inflammatory Drugs after OcularSurgery,” (2000) 118:1129-1132)) at about the same dosage. In someembodiments, the compounds of Formula A-D-Y, or pharmaceuticallyacceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof,are compounds with reduced risk of corneal melt.

The compounds and compositions described herein can be used in methodsfor treating diseases of the eye. One example is ovarian cancer. Ovariancancer is the most lethal gynecologic cancer, affecting women of allages. About 95% are epithelial ovarian cancers (referred to here asOvCa); germ cell tumors and sex cord-stromal tumors comprise theremainder. The 5-year survival is only 17%-28% for those withadvanced-stage tumors.

For a minority of ovarian cancer patients, surgery is curative. Allothers are treated with cytoreductive surgery plus chemotherapy with acombination of cisplatin and paclitaxel, which achieves a response rateof ˜80%. About 70% of patients with stage III or IV ovarian cancer recurwithin 5 years and drug resistance emerges. Patients with a relapse-freeinterval of >6 months are considered “cisplatin-sensitive” while thosewho progress on or relapse within 6 months of the initial therapy areconsidered “cisplatin-resistant.” Patients with resistant disease aretreated with other agents, such as liposomal doxorubicin, gemcitabine,topotecan, or etoposide. The overall response rates with these drugs are10%-25% and the duration of response is short.

Available drugs have reached a therapeutic ceiling. During the last 20years the extension in overall survival has been sluggish, Sadly, recenttargeted therapies of ovarian cancer. e.g., PARP inhibitors. anti-TNFantibodies and folate antagonists. have extended overall survivalminimally or not at all. Thus novel agents are required to improveoutcomes for advanced ovarian cancer.

The compounds and compositions described herein can be used in methodsfor treating diseases of the eye. In some embodiments, the diseases ofthe eye that are treated by the compounds, compositions, methods, andkits described herein include dry eye disease and retinopathy. In someembodiments, retinopathy may include the diseases of diabeticretinopathy, retinopathy of prematurity, VEGF retinopathy, age relatedmacular degeneration, retinal vein occlusion, and/or hypertensiveretinopathy. In certain embodiments, retinopathy may be diabeticretinopathy.

Dry eye disease (DED) is a multi-factorial disease of the ocular surfacecharacterized by loss of homeostasis of the tear film and accompanied byocular symptoms. The tear film in DED is abnormal because of one or moreof three reasons: tear production is decreased; tear evaporation isincreased; or the mucus or lipids of the tear are abnormal. The clinicalmanifestations of DED can vary in severity from very mild to the pointthat they decrease the ability to perform activities requiring visualattention such as reading and driving, seriously affecting the patient'squality of life. Given its worldwide distribution and the lack of asingle definitive test or consensus of criteria for its diagnosis,prevalence figures for DED vary. The best estimate of its prevalence is15% (17.9% for women and 10.5% for men); some authors consider even 15%an underestimate.

DED is an inflammatory disease whose pathogenesis is under extensivestudy. For example, dysfunction of the tear glands, chronic irritativestress or systemic autoimmune diseases can lead to ocular inflammation.In turn, inflammation causes dysfunction or death of cells responsiblefor tear secretion establishing a vicious cycle, which, regardless ofthe initiating insult, leads to ocular surface disease. The importantcontributors to the inflammatory process in DED are: (1) activation ofpro-inflammatory cytokines; tear hyperosmolarity, which stimulatesinflammatory mediators through MAPKs; (2) matrix metalloproteinases(MMPs), which lyse components of the corneal epithelial basementmembrane and tight junction proteins; (3) chemokines, which recruitnearby responsive cells; and (4) T cells, which can amplify the cascadeby attracting inflammatory cells, e.g., in Sjögren's syndrome.

The treatment of DED depends on its clinical severity. The symptoms ofvery mild disease are often treated with artificial tears, which providepartial relief but do not suppress inflammation. Advanced disease ismanaged with the immunosuppressant cyclosporine, the recently approvedintegrin antagonist lifitegrast, punctal plugs, or rarelycorticosteroids. Non-steroidal anti-inflammatory drugs (NSAIDs) have norole in DES.

Diabetic retinopathy refers to retinal changes that occur in patientswith diabetes mellitus. These changes affect the small blood vessels ofthe retina and can lead to vision loss through several differentpathways. Macular edema, defined as retinal thickening and edemainvolving the macula can occur at any stage of diabetic retinopathy.Diabetic retinopathy is one of the commonest causes of vision loss.Vascular endothelial growth factor (VEGF) is secreted by ischemicretina. VEGF leads to (a) increased vascular permeability resulting inretinal swelling/edema and (b) angiogenesis—new blood vessel formation.In some embodiments, agents that suppress VEGF can control diabeticretinopathy.

In addition to diabetic retinopathy, several other ocular diseases arecharacterized by abnormal vascular phenomena that are predominantlydependent on VEGF. Given the role of VEGF in these disorders,controlling VEGF is an approach to their prevention and treatment.Prominent among them is age-related macular degeneration (AMD), adegenerative disease of the central portion of the retina (the macula)that results primarily in loss of central vision. Central vision isrequired for activities such as driving, reading, watching television,and performing activities of daily living. AMD is classified as dry(atrophic) or wet (neovascular or exudative) for clinical purposes. WetAMD, also referred to as choroidal neovascularization is characterizedby growth of abnormal vessels into the subretinal space, usually fromthe choroidal circulation and less frequently from the retinalcirculation. These abnormal blood vessels leak, leading to collectionsof subretinal fluid and/or blood beneath the retina.

Retinal vein occlusion (RVO) is an important cause of visual loss amongolder adults throughout the world. An important component of RVO are itssecondary complications that affect vision, including macular edema,retinal neovascularization, and anterior segment neovascularization.VEGF pays a crucial role in these vision-determining complications.Patients with severe (ischemic) central retinal vein occlusion are atparticularly high risk for neovascular glaucoma, often within the firstfew months of diagnosis, and should be observed at least monthly fordevelopment of anterior segment neovascularization during this period.Indeed, patients with severe (ischemic) central retinal vein occlusionare at particularly high risk for neovascular glaucoma, and are observedclosely for development of anterior segment neovascularization. VEGFinhibitors in patients with RVO are hypothesized to limit macular edemaand improve vision by decreasing vascular permeability.

Without wishing to be bound by any particular theory, the invention isbased at least in part on several unexpected observations relating tothe combination of compounds of Formula A-D-Y, or pharmaceuticallyacceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof,with anti-infective agents. In some embodiments, such combinations canbe used to treat ocular conditions. In some embodiments, certainchemical moieties in the compounds of Formula A-D-Y, for example “A,”are residues relating to nonsteroidal anti-inflammatory active compounds(NSAIDs). However, in some embodiments, the compounds of Formula A-D-Ydo not behave like NSAIDs when applied to the eye. For example, in someembodiments, compounds of Formula A-D-Y do not inhibit the synthesis ofprostaglandins in the eye, as is typically the case with NSAIDs. Inother embodiments, the compounds of Formula A-D-Y do not cause cornealmelt, which is a complication of ocular application of NSAIDs, and whichtypically prohibits or restricts the use of topical ophthalmic NSAIDs.However, the compounds of Formula A-D-Y of the current inventionunexpectedly possess beneficial analgesic properties similar to NSAIDs.In some embodiments, the compounds of Formula A-D-Y of the currentinvention provide corneal analgesia. In some embodiments, the compoundsof Formula A-D-Y of the current invention provide short-term cornealanalgesia. Thus, in some embodiments, the compounds of Formula A-D-Y ofthe current invention provide symptomatic relief from the oculardiscomfort associated with various ophthalmic diseases or disorders. Insome embodiments, the compounds of Formula A-D-Y of the currentinvention do not inhibit the antibacterial efficacy of antibioticsadministered in a combination.

Efficacy of the compounds and combinations of compounds described hereinin treating the indicated diseases or disorders can be tested usingvarious models known in the art, and described herein, which provideguidance for treatment of human disease. Any and all of the describedmethods of treatment may include medical follow-up to determine thetherapeutic or prophylactic effect brought about in the subjectundergoing treatment with the compound(s) and/or composition(s)described herein.

Pharmaceutical Compositions

In an embodiment, an active pharmaceutical ingredient or combination ofactive pharmaceutical ingredients, such as any of the compounds ofFormula A-D-Y of the invention, is provided as a pharmaceuticallyacceptable composition.

In one embodiment, the invention relates to a pharmaceutical compositionincluding a therapeutically effective amount of a compound of FormulaA-D-Y for the treatment of a disease alleviated by administering acompound of Formula A-D-Y in a patient in need thereof, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, and a physiologically compatible carrier medium.

In one embodiment, the invention relates to a pharmaceutical compositionincluding a therapeutically effective amount of a compound of FormulaA-D-Y for the treatment of a disease alleviated by administering acompound of Formula A-D-Y in a patient in need thereof, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, and a physiologically compatible carrier medium,wherein the disease is cancer or an inflammatory disease. In oneembodiment, the disease is rheumatoid arthritis, a cardiovasculardisease, multiple sclerosis, inflammatory bowel disease, chronicobstructive pulmonary disease (COPD), asthma, acute respiratory distresssyndrome (ARDS), or acute lung injury (ALI). In one embodiment, thediseases is a cancer such as acoustic neuroma, adenocarcinoma,angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma,bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma,cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectalcancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma,endotheliocarcinoma, ependymoma, epithelial carcinoma, esophagealcancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastomamultiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma,kidney cancer, leiomyosarcoma, liposarcoma, lung cancer,lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasalcancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma,papillary carcinoma, pinealoma, prostate cancer, rabdomyosarcoma, rectalcancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous glandcarcinoma, seminoma, skin cancer, squamous cell carcinoma, stomachcancer, sweat gland carcinoma, synovioma, testicular cancer, small celllung carcinoma, throat cancer, uterine cancer, Wilm's tumor, bloodcancer, acute erythroleukemic leukemia, acute lymphoblastic B-cellleukemia, acute lymphoblastic T-cell leukemia, acute lymphoblasticleukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia,acute myeloblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocytic leukemia, acute promyelocytic leukemia, acuteundifferentiated leukemia, chronic lymphocytic leukemia, chronicmyelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chaindisease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma,polycythemia vera, or Waldenstrom's macroglobulinemia.

In some embodiments, the compositions described herein may be formulatedfor administration topically to the eye and surrounding tissues,particularly to the inner surface of the eye and the inner surface ofthe eyelids, including e.g., cornea, conjunctiva and sclera. Suchcompositions, for example, may be formulated for instillationadministration, administration into conjunctival sac and conjunctivaladministration. In particular, the compositions described herein may beformulated as eye drops. Such eye drop formulations may include a liquidor semisolid pharmaceutical composition adapted to administration to theeye. A typical example of an eye drop composition is an ophthalmicsolution to be administered dropwise to the eye.

In some embodiments, the concentration of each of the activepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as any of the compounds of Formula A-D-Y of theinvention, is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%,40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w,w/v, or v/v of the pharmaceutical composition.

In some embodiments, the concentration of each of the activepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as any of the compounds of Formula A-D-Y of theinvention, is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of thepharmaceutical composition.

In some embodiments, the concentration of each of the activepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as any of the compounds of Formula A-D-Y of theinvention, is in the range from about 0.0001% to about 50%, about 0.001%to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%,about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% toabout 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5%to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w,w/v, or v/v of the pharmaceutical composition.

In some embodiments, the concentration of each of the activepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as any of the compounds of Formula A-D-Y of theinvention, is in the range from about 0.001% to about 10%, about 0.01%to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%,about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about1%, about 0.1% to about 0.9% w/w, w/v, or v/v of the pharmaceuticalcomposition.

In some embodiments, the concentration of each of the activepharmaceutical ingredients provided in the pharmaceutical compositionsof the invention, such as any of the compounds of Formula A-D-Y of theinvention, is about 1%, about 2%, about 3%, about 4%, about 5%, about6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%,about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%,about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%,about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%,about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%,about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%,about 98%, about 99%, or about 100%.

In some embodiments, the amount of each of the active pharmaceuticalingredients provided in the pharmaceutical compositions of theinvention, such as any of the foregoing compounds of Formula A-D-Y ofthe invention, is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g,2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g,0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of each of the active pharmaceuticalingredients provided in the pharmaceutical compositions of theinvention, such as any of the compounds of Formula A-D-Y of theinvention, is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5, 4 g, 4.5 g, g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

Each of the active pharmaceutical ingredients according to the inventionis effective over a wide dosage range. For example, in the treatment ofadult humans, dosages independently range from 0.01 to 1000 mg, from 0.5to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day areexamples of dosages that may be used. The exact dosage will depend uponthe route of administration, the form in which the compound isadministered, the gender and age of the subject to be treated, the bodyweight of the subject to be treated, and the preference and experienceof the attending physician. The clinically-established dosages of thecompounds of Formula A-D-Y of the invention may also be used ifappropriate.

In an embodiment, the molar ratio of two active pharmaceuticalingredients in the pharmaceutical compositions is in the range from 10:1to 1:10, preferably from 2.5:1 to 1:2.5, and more preferably about 1:1.In an embodiment, the weight ratio of the molar ratio of two activepharmaceutical ingredients in the pharmaceutical compositions isselected from the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1,15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1,2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12,1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20. In an embodiment,the weight ratio of the molar ratio of two active pharmaceuticalingredients in the pharmaceutical compositions is selected from thegroup consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1,12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3,1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16,1:17, 1:18, 1:19, and 1:20.

In an embodiment, the pharmaceutical compositions described herein, suchas any of the compounds of Formula A-D-Y of the invention, are for usein the treatment of an inflammation disease or disorder, a cancer, aneurodegenerative diseases or disorder, a cardiovascular disease ordisorder, an ocular disease or disorder, or an angiogenic disease ordisorder. In an embodiment, the pharmaceutical compositions describedherein, such as any of the compounds of Formula A-D-Y of the invention,are for use in the treatment of ovarian cancer, colon cancer, leukemia,gastric cancer, lung cancer, pancreatic cancer, or a cancercharacterized by a K-Ras mutation. In an embodiment, the pharmaceuticalcompositions described herein, such as any of the compounds of FormulaA-D-Y of the invention, are for use in the treatment of a cancerchemoresistant to other therapeutic agents, for example cisplatin, ortaxol. In an embodiment, the pharmaceutical compositions describedherein, such as any of the compounds of Formula A-D-Y of the invention,are for use in the treatment of diabetic retinopathy.

In an embodiment, the pharmaceutical compositions described herein, suchas any of the compounds of Formula A-D-Y of the invention, are for usein the treatment of hyperproliferative disorders associated with theoverexpression or up- and/or downregulation of VEGF and/or K-Ras. In asome embodiments, the pharmaceutical compositions described herein arefor use in the treatment of a cancer associated with overexpression orup- and/or downregulation of VEGF and/or K-Ras, such as pancreaticcancer, breast cancer, prostate cancer, lymphoma, skin cancer, coloncancer, melanoma, malignant melanoma, ovarian cancer, brain cancer,primary brain carcinoma, head-neck cancer, glioma, glioblastoma, livercancer, bladder cancer, non-small cell lung cancer, head or neckcarcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma,small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicularcarcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma,colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroidcarcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenalcarcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortexcarcinoma, malignant pancreatic insulinoma, malignant carcinoidcarcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia,cervical hyperplasia, leukemia, acute lymphocytic leukemia, chroniclymphocytic leukemia, acute myelogenous leukemia, chronic myelogenousleukemia, chronic granulocytic leukemia, acute granulocytic leukemia,hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma,polycythemia vera, essential thrombocytosis, Hodgkin's disease,non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primarymacroglobulinemia, or retinoblastoma.

In an embodiment, the invention includes a composition for treating anophthalmic condition in a patient in need thereof, wherein theophthalmic condition is selected from the group consisting of dry eyedisease and retinopathy, the composition comprising a therapeuticallyeffective amount of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, the compositions described herein include apharmaceutically acceptable carrier. In some embodiments, thecompositions described herein include one or more of a solubilizingagent, an alcohol, an acid, and a preservative.

In some embodiments, the compositions described herein include asolubilizing agent and an alcohol. In some embodiments, the compositionsdescribed herein include a solubilizing agents and an acid. In someembodiments, the compositions described herein include a solubilizingagents and a preservative. In some embodiments, the compositionsdescribed herein include a solubilizing agent, an alcohol, and an acid.In some embodiments, the compositions described herein include asolubilizing agent, an alcohol, an acid, and a preservative.

In some embodiments, the compositions of the invention may include acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, in an amount, byweight, of about 0.5% to about 75%, or about 0.5% to about 70%, or about0.5% to about 65%, or about 0.5% to about 60%, or about 0.5% to about55%, or about 0.5% to about 50%, or about 0.5% to about 45%, or about0.5% to about 40%, or about 0.5% to about 35%, or about 0.5% to about30%, or about 0.5% to about 25%, or about 0.5% to about 20%, or about0.5% to about 15%, or about 0.5% to about 10%, or about 0.5% to about9%, or about 0.5% to about 8%, or about 0.5% to about 7%, or about 0.5%to about 6%, or about 0.5% to about 5%, or about 0.5% to about 4%, orabout 0.5% to about 3%, or about 0.5% to about 2%, or about 0.5% toabout 1%.

In some embodiments, the solubilizing agent is vitamin E TPGS(d-α-tocopheryl polyethylene glycol 1000 succinate). In someembodiments, the compositions described herein include a solubilizingagent in an amount, by weight, of about 0.5% to about 75%, or about 1%to about 70%, or about 1% to about 65%, or about 1% to about 60%, orabout 1% to about 55%, or about 1% to about 50%, or about 1% to about45%, or about 1% to about 40%, or about 1% to about 35%, or about 1% toabout 30%, or about 1% to about 25%, or about 1% to about 20%, or about1% to about 15%, or about 1% to about 10%, or about 1% to about 5%.

In some embodiments, the alcohol is a sugar alcohol, such as mannitol.In some embodiments, the compositions described herein include analcohol in an amount by weight, of about 0.5% to about 75%, or about0.5% to about 70%, or about 0.5% to about 65%, or about 0.5% to about60%, or about 0.5% to about 55%, or about 0.5% to about 50%, or about0.5% to about 45%, or about 0.5% to about 40%, or about 0.5% to about35%, or about 0.5% to about 30%, or about 0.5% to about 25%, or about0.5% to about 20%, or about 0.5% to about 15%, or about 0.5% to about10%, or about 0.5% to about 9%, or about 0.5% to about 8%, or about 0.5%to about 7%, or about 0.5% to about 6%, or about 0.5% to about 5%, orabout 0.5% to about 4%, or about 0.5% to about 3%, or about 0.5% toabout 2%, or about 0.5% to about 1%.

In some embodiments, the acid is boric acid. In some embodiments, thecompositions described herein include an acid in an amount, by weight,of about 0.5% to about 75%, or about 0.5% to about 70%, or about 0.5% toabout 65%, or about 0.5% to about 60%, or about 0.5% to about 55%, orabout 0.5% to about 50%, or about 0.5% to about 45%, or about 0.5% toabout 40%, or about 0.5% to about 35%, or about 0.5% to about 30%, orabout 0.5% to about 25%, or about 0.5% to about 20%, or about 0.5% toabout 15%, or about 0.5% to about 10%, or about 0.5% to about 9%, orabout 0.5% to about 8%, or about 0.5% to about 7%, or about 0.5% toabout 6%, or about 0.5% to about 5%, or about 0.5% to about 4%, or about0.5% to about 3%, or about 0.5% to about 2%, or about 0.5% to about 1%.

In some embodiments, the preservative is polyquaternium-1 (polyquad). Insome embodiments, the compositions described herein include apreservative in an amount, by weight, of about 0.001% to about 5%, orabout 0.001% to about 4%, or about 0.001% to about 3%, or about 0.001%to about 2%, or about 0.001% to about 1%, or about 0.001% to about 0.5%,or about 0.001% to about 0.1%, or about 0.001% to about 0.009%, or about0.001% to about 0.008%, or about 0.007%, or about 0.001% to about0.006%, or about 0.001% to about 0.005%.

In some embodiments, the compositions described herein may include agelling excipient, such as gellan gum or sodium alginate. In someembodiments, the compositions described herein include a gellingexcipient in an amount, by weight, of about 0.5% to about 20%, or about0.1% to about 15%, or about 0.1% to about 10%, or about 0.1% to about9%, or about 0.1% to about 8%, or about 0.1% to about 7%, or about 0.1%to about 6%, or about 0.1% to about 5%, or about 0.1% to about 4%, orabout 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% toabout 1%, or about 0.1% to about 0.9%, or about 0.1% to about 0.8%, orabout 0.1% to about 0.7%, or about 0.1% to about 0.6%, or about 0.1% toabout 0.5%.

In some embodiments, the compositions described herein may include apoloxamer. In some embodiments, the compositions described hereininclude a poloxamer in an amount, by weight, of about 1% to about 75%,or about 1% to about 70%, or about 1% to about 65%, or about 1% to about60%, or about 1% to about 55%, or about 1% to about 50%, or about 1% toabout 45%, or about 1% to about 40%, or about 1% to about 35%, or about1% to about 30%, or about 1% to about 25%, or about 1% to about 20%, orabout 1% to about 15%, or about 1% to about 10%, or about 1% to about9%, or about 1% to about 8%, or about 1% to about 7%, or about 1% toabout 6%, or about 1% to about 5%, or about 1% to about 4%, or about 1%to about 3%, or about 1% to about 2%.

In some embodiments, the compositions described herein include asurfactant, such as Tween 80 or polyoxyl stearate. In some embodiments,the compositions described herein include a surfactant in an amount, byweight, of about 0.01% to about 20%, or about 0.01% to about 15%, orabout 0.01% to about 10%, or about 0.01% to about 9%, or about 0.01% toabout 8%, or about 0.01% to about 7%, or about 0.01% to about 6%, orabout 0.01% to about 5%, or about 0.01% to about 4%, or about 0.01% toabout 3%, or about 0.01% to about 2%, or about 0.01% to about 1%, orabout 0.01% to about 0.5%, or about 0.01% to about 0.1%, or about 0.01%to about 0.09%, or about 0.01% to about 0.08%, or about 0.07%, or about0.01% to about 0.06%, or about 0.01% to about 0.05%.

In some embodiments, the compositions described herein include acyclodextrin, such as (2-hydroxypropyl)-β-cyclodextrin. In someembodiments, the compositions described herein include a cyclodextrin inamount, by weight, of about 0.5% to about 95%, or about 0.5% to about90%, or about 0.5% to about 85%, or about 0.5% to about 80%, or about0.5% to about 75%, or about 0.5% to about 70%, or about 0.5% to about65%, or about 0.5% to about 60%, or about 0.5% to about 55%, or about0.5% to about 50%, or about 0.5% to about 45%, or about 0.5% to about40%, or about 0.5% to about 35%, or about 0.5% to about 30%, or about0.5% to about 25%, or about 0.5% to about 20%, or about 0.5% to about15%, or about 0.5% to about 10%, or about 0.5% to about 9%, or about0.5% to about 8%, or about 0.5% to about 7%, or about 0.5% to about 6%,or about 0.5% to about 5%, or about 0.5% to about 4%, or about 0.5% toabout 3%, or about 0.5% to about 2%, or about 0.5% to about 1%.

In an embodiment, the compositions described herein may include atherapeutically effective amount of a compound of Formula A-D-Y, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, and one or more of a gelling excipient, e.g., gellangum or sodium alginate, a poloxamer, a solubilizing agent, e.g., vitaminE TPGS, a surfactant, e.g., Tween 80 or polyoxyl stearate, a polyether,e.g., a polyethylene glycol, propylene glycol, Cremophor, and acyclodextrin, e.g., (2-hydroxypropyl)-β-cyclodextrin. In someembodiments, such formulations may allow for delivery of PS to anteriorsegments of the eye following topical administration. In someembodiments, such formulations may be used to deliver PS to the anteriorsegments of the eye in an amount sufficient to treat a disease describedherein that is associated with such anterior segments of the eye, i.e.,a therapeutically effective amount.

In certain embodiments, a substantial portion of the total compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, that is distributed to the tissues after1 hour, as determined by HPLC, is in a particular, or targeted, tissueor area. In certain embodiments, greater than 30% of the total compoundof Formula A-D-Y, or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, in the cornea, conjunctiva,aqueous humor, vitreous body, retina, choroid, sclera, lacrimal glandand lens, referred to as tissues or areas of the eye, can be found in asingle tissue or area of the eye. In certain embodiments, greater than30% of the total compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, in thecornea, conjunctiva, aqueous humor, vitreous body, retina, choroid,sclera, lacrimal gland and lens can be found in a single tissue or area.In certain embodiments, greater than 40% of the total compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, in the cornea, conjunctiva, aqueoushumor, vitreous body, retina, choroid, sclera, lacrimal gland and lenscan be found in a single tissue or area. In certain embodiments, greaterthan 50% of the total compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, in thecornea, conjunctiva, aqueous humor, vitreous body, retina, choroid,sclera, lacrimal gland and lens can be found in a single tissue or area.In certain embodiments, greater than 60% of the total compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, in the cornea, conjunctiva, aqueoushumor, vitreous body, retina, choroid, sclera, lacrimal gland and lenscan be found in a single tissue or area. In certain embodiments, greaterthan 70% of the total compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, in thecornea, conjunctiva, aqueous humor, vitreous body, retina, choroid,sclera, lacrimal gland and lens can be found in a single tissue or area.In certain embodiments, greater than 80% of the total compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, in the cornea, conjunctiva, aqueoushumor, vitreous body, retina, choroid, sclera, lacrimal gland and lenscan be found in a single tissue or area. In certain embodiments, greaterthan 90% of the total compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, in thecornea, conjunctiva, aqueous humor, vitreous body, retina, choroid,sclera, lacrimal gland and lens can be found in a single tissue or area.

As used herein, an amount described as “about 0%,” by weight, isunderstood to be an amount that is greater than 0%.

Described below are non-limiting pharmaceutical compositions and methodsfor preparing the same.

Pharmaceutical Compositions for Oral Administration

In an embodiment, the invention provides a pharmaceutical compositionfor oral administration containing the active pharmaceutical ingredientor combination of active pharmaceutical ingredients, such as thecompounds of Formula A-D-Y described herein, and a pharmaceuticalexcipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof an active pharmaceutical ingredient or combination of activepharmaceutical ingredients, and (ii) a pharmaceutical excipient suitablefor oral administration. In selected embodiments, the compositionfurther contains (iii) an effective amount of a third activepharmaceutical ingredient, and optionally (iv) an effective amount of afourth active pharmaceutical ingredient.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, sachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, a water-in-oil liquid emulsion, powders for reconstitution,powders for oral consumptions, bottles (including powders or liquids ina bottle), orally dissolving films, lozenges, pastes, tubes, gums, andpacks. Such dosage forms can be prepared by any of the methods ofpharmacy, but all methods include the step of bringing the activeingredient(s) into association with the carrier, which constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient(s) withliquid carriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation. Forexample, a tablet can be prepared by compression or molding, optionallywith one or more accessory ingredients. Compressed tablets can beprepared by compressing in a suitable machine the active ingredient in afree-flowing form such as powder or granules, optionally mixed with anexcipient such as, but not limited to, a binder, a lubricant, an inertdiluent, and/or a surface active or dispersing agent. Molded tablets canbe made by molding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent.

The invention further encompasses anhydrous pharmaceutical compositionsand dosage forms since water can facilitate the degradation of somecompounds. For example, water may be added (e.g., 5%) in thepharmaceutical arts as a means of simulating long-term storage in orderto determine characteristics such as shelf-life or the stability offormulations over time. Anhydrous pharmaceutical compositions and dosageforms of the invention can be prepared using anhydrous or low moisturecontaining ingredients and low moisture or low humidity conditions.Pharmaceutical compositions and dosage forms of the invention whichcontain lactose can be made anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions may be packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Each of the active pharmaceutical ingredients can be combined in anintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier can takea wide variety of forms depending on the form of preparation desired foradministration. In preparing the compositions for an oral dosage form,any of the usual pharmaceutical media can be employed as carriers, suchas, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols,or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. For example, suitablecarriers include powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets whichdisintegrate in the bottle. Too little may be insufficient fordisintegration to occur, thus altering the rate and extent of release ofthe active ingredients from the dosage form. Thus, a sufficient amountof disintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) may be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used may vary based upon the type of formulation and modeof administration, and may be readily discernible to those of ordinaryskill in the art. About 0.5 to about 15 weight percent of disintegrant,or about 1 to about 5 weight percent of disintegrant, may be used in thepharmaceutical composition. Disintegrants that can be used to formpharmaceutical compositions and dosage forms of the invention include,but are not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, sodium stearyl fumarate, mineral oil,light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol,other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenatedvegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesameoil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate,ethylaureate, agar, or mixtures thereof. Additional lubricants include,for example, a syloid silica gel, a coagulated aerosol of syntheticsilica, silicified microcrystalline cellulose, or mixtures thereof. Alubricant can optionally be added in an amount of less than about 0.5%or less than about 1% (by weight) of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active pharmaceutical ingredient(s) may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts,fusidic acid salts, fatty acid derivatives of amino acids,oligopeptides, and polypeptides, glyceride derivatives of amino acids,oligopeptides, and polypeptides, lecithins and hydrogenated lecithins,lysolecithins and hydrogenated lysolecithins, phospholipids andderivatives thereof, lysophospholipids and derivatives thereof,carnitine fatty acid ester salts, salts of alkylsulfates, fatty acidsalts, sodium docusate, acyl-lactylates, mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides, succinylated mono- anddi-glycerides, citric acid esters of mono- and di-glycerides, andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample, lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof, carnitine fatty acid ester salts, salts ofalkylsulfates, fatty acid salts, sodium docusate, acyllactylates, mono-and di-acetylated tartaric acid esters of mono- and di-glycerides,succinylated mono- and di-glycerides, citric acid esters of mono- anddi-glycerides, and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides, alkylmaltosides, alkylthioglucosides, laurylmacrogolglycerides, polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols, polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters, polyethylene glycol glycerol fatty acidesters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters,hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylenesterols, derivatives, and analogs thereof, polyoxyethylated vitamins andderivatives thereof, polyoxyethylene-polyoxypropylene block copolymers,and mixtures thereof, polyethylene glycol sorbitan fatty acid esters andhydrophilic transesterification products of a polyol with at least onemember of the group consisting of triglycerides, vegetable oils, andhydrogenated vegetable oils. The polyol may be glycerol, ethyleneglycol, polyethylene glycol, sorbitol, propylene glycol,pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate,sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols, glycerol fatty acid esters, acetylated glycerol fatty acidesters, lower alcohol fatty acids esters, propylene glycol fatty acidesters, sorbitan fatty acid esters, polyethylene glycol sorbitan fattyacid esters, sterols and sterol derivatives, polyoxyethylated sterolsand sterol derivatives, polyethylene glycol alkyl ethers, sugar esters,sugar ethers, lactic acid derivatives of mono- and di-glycerides,hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols, oil-solublevitamins/vitamin derivatives, and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In an embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use—e.g., compositions for injection. A solubilizer may also beadded to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives,ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG, amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ϵ-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone, esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof, and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals and alkaline earth metals. Example may include, but notlimited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

In some embodiments, a pharmaceutical composition is provided forinjection containing an active pharmaceutical ingredient or combinationof active pharmaceutical ingredients, such as a compound of FormulaA-D-Y, and a pharmaceutical excipient suitable for injection.

The forms in which the compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (andsuitable mixtures thereof), cyclodextrin derivatives, and vegetable oilsmay also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, for the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

Sterile injectable solutions are prepared by incorporating an activepharmaceutical ingredient or combination of active pharmaceuticalingredients in the required amounts in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certaindesirable methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Pharmaceutical Compositions for Topical Delivery

In some embodiments, a pharmaceutical composition is provided fortransdermal delivery containing an active pharmaceutical ingredient orcombination of active pharmaceutical ingredients, such as compounds ofFormula A-D-Y described herein, and a pharmaceutical excipient suitablefor topical, for example transdermal delivery, or transcorneal delivery.Any ocular drug delivery systems known in the art can be used to deliverthe compounds and compositions of the invention (Patel et al., “Oculardrug delivery systems: An overview,” World J Pharmacol. 2013; 2(2):47-64).

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of an active pharmaceutical ingredient or combination of activepharmaceutical ingredients in controlled amounts, either with or withoutanother active pharmaceutical ingredient.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445, and 5,001,139, the entirety of which areincorporated herein by reference. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.

Pharmaceutical Compositions for Inhalation

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra and the compounds of Formula A-D-Y described herein. Preferablythe compositions are administered by the oral or nasal respiratory routefor local or systemic effect. Compositions in preferablypharmaceutically acceptable solvents may be nebulized by use of inertgases. Nebulized solutions may be inhaled directly from the nebulizingdevice or the nebulizing device may be attached to a face mask tent, orintermittent positive pressure breathing machine. Solution, suspension,or powder compositions may be administered, preferably orally ornasally, from devices that deliver the formulation in an appropriatemanner. Dry powder inhalers may also be used to provide inhaled deliveryof the compositions.

Other Pharmaceutical Compositions and Formulations

Pharmaceutical compositions of the compounds of Formula A-D-Y describedherein may also be prepared from compositions described herein and oneor more pharmaceutically acceptable excipients suitable for sublingual,buccal, rectal, intraosseous, intraocular, intranasal, epidural, orintraspinal administration. Preparations for such pharmaceuticalcompositions are well-known in the art. See, e.g., Anderson, Philip O.;Knoben, James E.; Troutman, William G, eds., Handbook of Clinical DrugData, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds.,Principles of Drug Action, Third Edition, Churchill Livingston, N.Y.,1990, each of which is incorporated by reference herein in its entirety.

Administration of an active pharmaceutical ingredient or combination ofactive pharmaceutical ingredients or a pharmaceutical compositionthereof can be effected by any method that enables delivery of thecompounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g., transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. The active pharmaceutical ingredient or combinationof active pharmaceutical ingredients can also be administeredintraadiposally or intrathecally. In some embodiments, a compound ofFormula A-D-Y, or a pharmaceutical composition thereof, can beadministered intraperitoneally.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Exemplary liquid formulations include ophthalmic solutions,microemulsions, and in-situ gel formulations. Various excipients can beused in these formulations, for example excipients for regulatingosmotic pressure, pH, and/or viscosity of the formulation. In someembodiments, formulations are designed to extend the contact time ofliquid dosage forms with ocular tissues and to increase the tissueuptake of an active pharmaceutical ingredient. In some embodiments, suchexcipients are included in order to increase viscosity, and/or enhancepenetration. In some embodiments, cyclodextrins are added. Cyclodextrinsare cyclic oligosaccharides that form inclusion complexes with activepharmaceutical ingredients, thus increasing their aqueous solubility andbioavailability. In some embodiments, such approaches are useful forformulating hydrophobic active pharmaceutical ingredients.

In some embodiments, the invention relates to a liquid formulationincluding from about 0.05% to about 25%, for example about 3.5%, of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments,the liquid formulation includes from about 0.05% to about 25%, forexample about 16%, vitamin E TPGS. In some embodiments, the liquidformulation includes from about 0.05% to about 25%, for example about3.18%, mannitol. In some embodiments, the liquid formulation includesfrom about 0.05% to about 25%, for example about 1.2%, boric acid. Insome embodiments, the liquid formulation includes from about 0.001% toabout 2.5%, for example about 0.005% polyquaternium-1. In someembodiments, the liquid formulation includes from about 0.001% to about2.5%, for example 0.005% of a preservative. In some embodiments, theformulation can be made by dissolving polyquaternium-1 and vitamin ETPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) in purifiedwater, adding a compound of Formula A-D-Y to the solution, and stirringat 70° C. for a period of time, for example 30 min. The solution is thencentrifuged, for example at 13,200 rpm for a period of time, for example10 min, and the supernatant is collected. Mannitol and boric acid areadded to the harvested supernatant. Purified water is added to the finalsolution after pH adjustment to 6.7±0.2 using an alkali, for exampleNaOH.

In some embodiments, the invention relates to a liquid formulationincluding from about 0.05% to about 25%, for example from about 3% toabout 4% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, the invention relates to a liquid formulationincluding from about 5% to about 95%, for example about 80%,2-hydroxypropyl)-β-cyclodextrin (HP-β-CD). In some embodiments, theinvention relates to a liquid formulation including from about 0.05% toabout 5%, for example about 0.1% Cremophor EL (F1). In some embodiments,the invention relates to a liquid formulation including from about 0.05%to about 5%, for example about 1% Tween 80 (F2). In some embodiments,the formulation can be made by dissolving HP-β-CD (CAS No 128446-35-5),about 6 g, in 5 mL of purified water at 55° C. (on water bath). Anamount of a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof is added to thesolution, and the mixture is kept at 55° C. on a water bath overnight,or until the compound of Formula A-D-Y is fully dissolved. Kolliphor ELor Tween 80 is respectively added into the. The solution is thencentrifuged at 3000 rpm for about 10 min to remove undissolvedparticles. The supernatant is collected.

In some embodiments, the invention relates to a liquid formulationincluding from about 0.05% to about 25%, for example from about 3% toabout 4%, or about 3.5%, of a compound of Formula A-D-Y, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In some embodiments, the invention relates to a liquidformulation including from about 90% to about 99%, for example about96.5% propylene glycol (PG). In some embodiments, propylene glycol iswell tolerated by the eye. The formulation can be administered topicallyto the eyes of New Zealand white rabbits as a 3.5% compound of FormulaA-D-Y concentration in propylene glycol, as eye drops, and its 1-hourbiodistribution determined by HPLC thereafter.

In some embodiments, each of the various exemplary formulationsexemplified herein targets a compound described herein, for example acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, to specific oculartissues in a specific manner. In some embodiments, the biodistributionprofiles of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof,formulated as described herein are the result of an inherentphysicochemical property of the compound, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, the biodistribution profiles of a compound of FormulaA-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, formulated as described herein are notthe result of an inherent physicochemical property of the compound, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof. In some embodiments, the biodistribution profiles of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, formulated as describedherein, result from the specific formulations described herein. In someembodiments, the formulations described herein can direct a compound ofFormula A-D-Y, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, to tissues of therapeutic interest, e.g.,cornea and conjunctiva for treatment of dry eye disease, or retina fortreatment of various retinopathies.

Exemplary semi-solid formulations include high viscosity formulationsthat increase bioavailability by increasing the residence time of theactive pharmaceutical ingredients in the precorneal area. In situ gelsare viscous liquids that undergo sol-to-gel transitions upon ocularapplication because of changes in pH, temperature or electrolyteconcentration. Gelling excipients with favorable mucoadhesive propertiesfurther increase the residence time. Polymers employed in developingthese drug formulations include gellan gum, poloxamer, and celluloseacetate phthalate. Thermogels can for example be generated usingpoloxamer 407 or gellan gum.

In some embodiments, the invention relates to a gel formulationincluding from about 0.05% to about 25%, for example from about 2.4% toabout 3% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, the invention relates to a gel formulation includingfrom about 0.05% to about 5%, for example about 0.4% or about 0.5%gellan gum. In some embodiments, the invention relates to a gelformulation including from about 0.05% to about 25%, for example about5% or about 10% vitamin E TPGS. In some embodiments, the inventionrelates to a gel formulation including from about 0.05% to about 25%,for example about 5% or about 10% (2-hydroxypropyl)-β-cyclodextrin. Insome embodiments, a gellan gum solution is prepared by adding anappropriate amount of gellan gum to deionized water and heating themixture to 90° C. with fast stirring (500 rpm). Once the gum iscompletely dissolved, the solution is filtered through a 0.22 μm filter.Then, the compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof, and additionalexcipients are added to the system to achieve the desired concentration,followed by stirring at 50° C. at 500 rpm until complete dissolution.

In some embodiments, the invention relates to a gel formulationincluding from about 0.05% to about 25%, for example about 3% of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and an alginate. Insome embodiments, the invention relates to a gel formulation includingfrom about 0.05% to about 5%, for example about 1.5% sodium alginate. Insome embodiments, the invention relates to a gel formulation includingfrom about 0.05% to about 25%, for example about 15% Tween 80. In someembodiments, the invention relates to a gel formulation including fromabout 0.05% to about 25%, for example about 10%(2-hydroxypropyl)-β-cyclodextrin. In some embodiments, the inventionrelates to a gel formulation including from about 0.05% to about 25%,for example about 10% polyethylene glycol 400 (PEG400). In someembodiments, the invention relates to a gel formulation including fromabout 0.05% to about 25%, for example about 5% polyoxyl stearate. Insome embodiments, a sodium alginate solution is prepared by adding anappropriate amount of sodium alginate to deionized water and heating themixture to 90° C. with fast stirring (500 rpm). Once sodium alginate iscompletely dissolved, the solution is filtered through a 0.22 μm filter.Then, a compound of Formula A-D-Y, or a pharmaceutically acceptablesalt, solvate, hydrate, cocrystal, or prodrug thereof and any additionalexcipients are added to achieve any desired concentration and stirred at50° C. at 500 rpm until complete dissolution.

In some embodiments, the invention relates to a nanoparticle formulationincluding from about 0.05% to about 25%, for example from about 3% toabout 3.5% of a compound of Formula A-D-Y, or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Insome embodiments, the invention relates to a nanoparticle formulationincluding from about 75% to about 99%, for example from about 96.5% toabout 97% methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA). Insome embodiments, an oil phase is prepared by dissolving an amount of acompound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and an amount ofPEG-PLA in 20 mL dichloromethane (DCM). In some embodiments, a waterphase is prepared by dissolving an amount of sodium cholate in an amountof purified water. Then an amount of oil phase is gently added into anamount of water phase in an Eppendorf conical tube. To create anemulsion, probe sonication can be used for an amount of time, forexample about for 2 min at 75% output (Branson 150, Fisher Scientific™,USA; watt output at about 12-13). The emulsion is then transferred intoa beaker and stirred overnight at about 600 rpm in a chemical hood untilthe DCM is fully evaporated. The mixture is then transferred intoultrafilter tubes (Amicon Ultra-15), centrifuged at 5000 rpm for about 1h. PBS is added into the resulting concentrated nanoparticle formulationin the ultrafilter tubes to a specific volume, and the centrifugationstep is repeated once. The concentrated nanoparticles are resuspendedinto PBS to a desired final volume, transferred to an Eppendorf tube andspun for a short period of time, for example a few seconds, to removeaggregates. The supernatant is harvested as the final product.Nanoparticles are characterized in terms of effective diameter (nm),particle size distribution (polydispersity index), drug encapsulationefficiency (EE; calculated as EE %=drug encapsulated/drug added×100).The compound of Formula A-D-Y formulated in nanoparticles isadministered topically as eye drops to New Zealand white rabbits, andthe biodistribution of the compound of Formula A-D-Y in ocular tissuesat various time points post administration is determined by HPLC.Biodistribution of a compound of Formula A-D-Y can also be determinedafter intravitreal injection. An amount of compound of Formula A-D-Yformulated in nanoparticles and diluted with PBS to about 0.2% to about2% concentration is injected directly into the vitreous of New Zealandwhite rabbits, and the biodistribution is determined by HPLC.Biodistribution of a compound of Formula A-D-Y in human eyes ex vivo canbe determined as described elsewhere herein. The anterior surface of thehuman eye (corresponding to an area slightly larger than the palpebralfissure) is brought into direct contact with a compound of Formula A-D-Ynanoparticle solution of a concentration of about 0.2%, about 1%, orabout 2%, then the tissue is processed as described herein.Biodistribution of a compound of Formula A-D-Y can also be determined inporcine eyes ex vivo. Explanted pig eyes are exposed to a compound ofFormula A-D-Y nanoparticle solution (concentration of about 2%) andtreated similar to the human eyes.

In some embodiments, the compounds of Formula A-D-Y of the invention arecapable of reaching the retina when applied topically to the anteriorsurface of the eye. In some embodiments, this unexpected property isrealized when the compound of Formula A-D-Y of the invention isformulated in as described herein. In some embodiments, the property ofa compound of Formula A-D-Y to be rapidly transported to the posteriorsegment of the eye can be changed, inhibited, or otherwise modulated bychanging its corresponding formulation. In some embodiments, theunexpected feature of restricting the distribution of a compound ofFormula A-D-Y can be used to direct the compound to a specific part ofthe entire eye. In some embodiments, a compound of Formula A-D-Y isdirected to the anterior segment of the eye. In some embodiments, acompound of Formula A-D-Y is directed to the posterior segment of theeye.

Exemplary multicompartment formulations include nanoparticles,liposomes, dendrimers, and niosomes. Nanoparticles are polymericcarriers, which improve bioavailability thanks to increased cornealpenetration and a larger surface area for dissolution. Niosomes anddiscosomes are two-layered carriers which increase active pharmaceuticalingredients bioavailability by extending precorneal residence time.

Kits

The invention also provides kits. The kits include an activepharmaceutical ingredient or combination of active pharmaceuticalingredients, either alone or in combination in suitable packaging, andwritten material that can include instructions for use, discussion ofclinical studies and listing of side effects. Such kits may also includeinformation, such as scientific literature references, package insertmaterials, clinical trial results, and/or summaries of these and thelike, which indicate or establish the activities and/or advantages ofthe composition, and/or which describe dosing, administration, sideeffects, drug interactions, or other information useful to the healthcare provider. Such information may be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials. The kit mayfurther contain another active pharmaceutical ingredient. In selectedembodiments, an active pharmaceutical ingredient or combination ofactive pharmaceutical ingredients are provided as separate compositionsin separate containers within the kit. In selected embodiments, anactive pharmaceutical ingredient or combination of active pharmaceuticalingredients are provided as a single composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and may be includedin the kit. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits may also, in selectedembodiments, be marketed directly to the consumer.

In some embodiments, the invention provides a kit including acomposition including a therapeutically effective amount of an activepharmaceutical ingredient (e.g., a compound of Formula A-D-Y) orcombination of active pharmaceutical ingredients or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. Thesecompositions are typically pharmaceutical compositions. The kit is forco-administration of the active pharmaceutical ingredient or combinationof active pharmaceutical ingredients, either simultaneously orseparately.

In some embodiments, the invention provides a kit including (1) acomposition including a therapeutically effective amount of an activepharmaceutical ingredient (e.g., a compound of Formula A-D-Y) orcombination of active pharmaceutical ingredients or a pharmaceuticallyacceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and(2) a diagnostic test for determining whether a patient's cancer is aparticular subtype of a cancer. Any of the foregoing diagnostic methodsmay be utilized in the kit.

The kits described above are preferably for use in the treatment of thediseases and conditions described herein. In some embodiments, the kitsare for use in the treatment of an inflammatory disease. In someembodiments, the kits are for use in the treatment of a cancer, aneurodegenerative diseases or disorder, a cardiovascular disease ordisorder, an ocular disease or disorder, an angiogenic disease ordisorder, ovarian cancer, colon cancer, leukemia, gastric cancer, lungcancer, pancreatic cancer, a cancer characterized by a K-Ras mutation, acancer chemoresistant to other therapeutic agents (e.g., cisplatin ortaxol), or diabetic retinopathy.

In a particular embodiment, the kits are for use in the treatment ofhyperproliferative disorders, such as cancer. In some embodiments, thekits described herein are for use in the treatment of a cancer selectedfrom the group consisting of pancreatic cancer, breast cancer, prostatecancer, lymphoma, skin cancer, colon cancer, melanoma, malignantmelanoma, ovarian cancer, brain cancer, primary brain carcinoma,head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer,non-small cell lung cancer, head or neck carcinoma, breast carcinoma,ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms'tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma,pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostaticcarcinoma, genitourinary carcinoma, thyroid carcinoma, esophagealcarcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cellcarcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignantpancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma,mycosis fungoides, malignant hypercalcemia, cervical hyperplasia,leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia,acute myelogenous leukemia, chronic myelogenous leukemia, chronicgranulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia,neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera,essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma,soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, andretinoblastoma. In particular embodiments, the kits described herein arefor use in the treatment of malignant melanoma.

Dosages and Dosing Regimens

The amounts of the pharmaceutical compositions administered using themethods herein, such as the dosages of compounds of Formula A-D-Y, willbe dependent on the subject, e.g., human or mammal being treated, theseverity of the disorder or condition, the rate of administration, thedisposition of the active pharmaceutical ingredients and the discretionof the prescribing physician. However, an effective dosage is in therange of about 0.001 to about 100 mg per kg body weight per day, such asabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, such as about 0.05 toabout 2.5 g/day. In some instances, dosage levels below the lower limitof the aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffect—e.g., by dividing such larger doses into several small doses foradministration throughout the day. The dosage of the pharmaceuticalcompositions and active pharmaceutical ingredients may be provided inunits of mg/kg of body mass or in mg/m² of body surface area.

In some embodiments, the compounds described herein are delivered tomammals for the treatment of disease. A person having ordinary skill inthe art would understand that, in certain embodiments, dosages of suchcompounds may be adjusted depending upon the mammal to be treated. Forexample, in certain embodiments, the treatment of rabbits is describedherein and such dosages may or may not be revised upon theadministration of the compounds of the invention to a human. However, aperson having ordinary skill in the art may, if necessary, convert thedosages provided herein as set forth in Guidance for Industry:Estimating the Maximum Safe Starting Dose in Initial Clinical Trials forTherapeutics in Adult Healthy Volunteers, U.S. Department of Health andHuman Services, Food and Drug Administration, Center for Drug Evaluationand Research (CDER), July 2005, the entirety of which is incorporatedherein by reference. In some embodiments, a human equivalent dose (HED)may be determined from an animal dose, the animal dose may be multipliedby the following conversion factors, to provide units in mg/kg:mouse=0.08, hamster=0.13, rat=0.16, ferret=0.19, guinea pig=0.22,rabbit=0.32, dog=0.54, monkey=0.32, marmoset=0.16, squirrel monkey=0.19,baboon=0.54, micro-pig=0.73, and mini-pig=0.95. The foregoing conversionfactors are exemplary and in no way limit the dosages provided herein aswould be understood by a person having ordinary skill in the art.

In some embodiments, the invention includes methods of treating a cancerin a human subject, the method comprising the steps of administering atherapeutically effective dose of an active pharmaceutical ingredientthat is a compound of Formula A-D-Y to the human subject.

In some embodiments, the invention includes methods of treating a cancerin a human subject suffering from the cancer in which cancer cellsoverexpress K-Ras, the method comprising the steps of administering atherapeutically effective dose of an active pharmaceutical ingredientthat is a compound of Formula A-D-Y to the human subject to inhibit ordecrease the activity of K-Ras protein.

In some embodiments, a pharmaceutical composition or activepharmaceutical ingredient is administered in a single dose. Suchadministration may be by injection, e.g., intravenous injection, inorder to introduce the active pharmaceutical ingredient quickly.However, other routes, including the preferred oral route, may be usedas appropriate. A single dose of a pharmaceutical composition may alsobe used for treatment of an acute condition.

In some embodiments, a pharmaceutical composition or activepharmaceutical ingredient is administered in multiple doses. In anembodiment, a pharmaceutical composition is administered in multipledoses. Dosing may be once, twice, three times, four times, five times,six times, or more than six times per day. Dosing may be once a month,once every two weeks, once a week, or once every other day. In otherembodiments, a pharmaceutical composition is administered about once perday to about 6 times per day. In some embodiments, a pharmaceuticalcomposition is administered once daily, while in other embodiments, apharmaceutical composition is administered twice daily, and in otherembodiments a pharmaceutical composition is administered three timesdaily.

Administration of the active pharmaceutical ingredients may continue aslong as necessary. In selected embodiments, a pharmaceutical compositionis administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 day(s). Insome embodiments, a pharmaceutical composition is administered for lessthan 28, 14, 7, 6, 5, 4, 3, 2, or 1 day(s). In some embodiments, apharmaceutical composition is administered chronically on an ongoingbasis—e.g., for the treatment of chronic effects. In some embodiments,the administration of a pharmaceutical composition continues for lessthan about 7 days. In yet another embodiment the administrationcontinues for more than about 6, 10, 14, 28 days, two months, sixmonths, or one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

In some embodiments, an effective dosage of an active pharmaceuticalingredient disclosed herein is in the range of about 1 mg to about 500mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg toabout 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about198 to about 202 mg. In some embodiments, an effective dosage of anactive pharmaceutical ingredient disclosed herein is less than about 25mg, less than about 50 mg, less than about 75 mg, less than about 100mg, less than about 125 mg, less than about 150 mg, less than about 175mg, less than about 200 mg, less than about 225 mg, or less than about250 mg. In some embodiments, an effective dosage of an activepharmaceutical ingredient disclosed herein is greater than about 25 mg,greater than about 50 mg, greater than about 75 mg, greater than about100 mg, greater than about 125 mg, greater than about 150 mg, greaterthan about 175 mg, greater than about 200 mg, greater than about 225 mg,or greater than about 250 mg.

In some embodiments, an effective dosage of an active pharmaceuticalingredient disclosed herein is in the range of about 0.01 mg/kg to about200 mg/kg, or about 0.1 to 100 mg/kg, or about 1 to 50 mg/kg.

In some embodiments, an active pharmaceutical ingredient is administeredat a dosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150,or 200 mg BID. In some embodiments, an active pharmaceutical ingredientis administered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15,25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.

In some instances, dosage levels below the lower limit of the aforesaidranges may be more than adequate, while in other cases still largerdoses may be employed without causing any harmful side effect, e.g., bydividing such larger doses into several small doses for administrationthroughout the day. As those skilled in the art will appreciate, thedosage actually administered will depend upon the condition beingtreated, the age, health and weight of the recipient, the type ofconcurrent treatment, if any, and the frequency of treatment. Moreover,the effective dosage amount may be determined by one skilled in the arton the basis of routine empirical activity testing to measure thebioactivity of the compound(s) in a bioassay, and thus establish theappropriate dosage to be administered.

An effective amount of the combination of the active pharmaceuticalingredient may be administered in either single or multiple doses by anyof the accepted modes of administration of agents having similarutilities, including rectal, buccal, intranasal and transdermal routes,by intra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, orally, topically, or asan inhalant.

In some embodiments, the compositions described herein further includecontrolled-release, sustained release, or extended-release therapeuticdosage forms for administration of the compounds described herein, whichinvolves incorporation of the compounds into a suitable delivery systemin the formation of certain compositions. This dosage form controlsrelease of the compound(s) in such a manner that an effectiveconcentration of the compound(s) in the bloodstream may be maintainedover an extended period of time, with the concentration in the bloodremaining relatively constant, to improve therapeutic results and/orminimize side effects. Additionally, a controlled-release system wouldprovide minimum peak to trough fluctuations in blood plasma levels ofthe compound.

The following examples describe the invention in further detail. Theseexamples are provided for illustrative purposes only, and should in noway be considered as limiting the invention.

EXAMPLES Materials and Methods

General Methods for Chemistry: All air or moisture sensitive reactionswere performed under positive pressure of nitrogen with oven-driedglassware. Chemical reagents and anhydrous solvents are obtained fromcommercial sources and used as-is. HPLC conditions: Column: Halo C184.6×150 mm, 2.7 μm, Part #: 92814-702; flow rate: 0.8 mL/min; mobilephase A: 0.05% TFA/water; B: 0.05% trifluoroacetic acid/acetonitrile;gradient: time (min)−% A/% B: 0 min=90%/10%; 8 min=20%/80%; 10 min0%/100%; 10.1 min=90%/10%; 15 min=90%/10%.

Example 1: Synthesis of Compound 1

Synthesis of intermediate (c): a mixture of sulindac (9.36 g, 26.2 mmol)and CDI (4.92 g, 30.1 mmol, 1.15 eq.) in THF (150 mL), was stirred atroom temperature for 1-2 h to generate a thick slurry. After thecomplete consumption of sulindac, compound (b) (7.83 g, 34.1 mmol, 1.30eq.) was added to the slurry. The resulting mixture was stirred at roomtemperature overnight to give a clear yellowish solution. After thereaction was complete as monitored by HPLC, the solvent was evaporatedunder reduced pressure at room temperature. EtOAc (200 mL) and H₂O (60.0mL) were then added to the reaction mixture. The organic layer waswashed with H₂O (40.0 mL×3), brine (30.0 mL), dried over MgSO₄, andevaporated to give intermediate (c) (17.2 g). The material was used inthe next step without further purification.

Synthesis of intermediate (d): to a solution of intermediate (c) (17.2g) in DCM (90.0 mL) was added TFA (35.0 mL) in ice bath. The resultingsolution was stirred overnight. After the reaction was complete asmonitored by HPLC, the reaction mixture was evaporated under reducedpressure at room temperature to give intermediate (d) (40.6 g withexcess TFA residue). The material was used in the next step withoutfurther purification.

Synthesis of compound 1: to a solution of intermediate (d) (36.8 g withexcess TFA, 23.7 mmol) in DCM (120 mL) in the presence of Et₃N (100 mL)in ice bath was added methanesulfonyl chloride (4.5 g, 1.5 eq.) in DCM(20 mL) over 4 h via a syringe pump. After the reaction was complete asmonitored by HPLC, the reaction mixture was diluted with DCM (150 mL),washed with NaHCO₃ (50 mL×2), H₂O (40 mL×3), brine (50 mL), andevaporated to give a reaction mixture with excess Et₃N residue. Thereaction mixture was dissolved in EtOAc (200 mL) and H₂O (100 mL) wereadded to the reaction mixture. The organic layer was washed with H₂O(40.0 mL×4), brine (40.0 mL×2), dried over MgSO₄, evaporated, andpurified by flash chromatography (0%-5% MeOH/DCM) to afford compound 1(4.86 g) (yield: 34.0% overall 3 steps).

Synthesis of compound 1 salt: a solution of compound 1 (7.86 g) in DCM(100 mL) was stirred at 0° C., then methanesulfonic acid (1.38 g, 1.0eq.) in DCM (10.0 mL) was added slowly. EtOAc (100 mL) was added to theabove mixture very slowly followed by heptane (200 mL). The resultingsuspension was stirred for 2 h, filtered, washed with heptane (30.0mL×3) to give yellow solid. This yellow solid was dried under highvacuum, then dissolved in H₂O (40 mL), freeze drying to furnish compound1 salt (8.4 g). FIG. 1 illustrates the ¹HNMR spectra of compound 1 salt,and FIG. 2 illustrates the MS of compound 1 salt.

Example 2: Synthesis of Compound 2

Synthesis of compound 2: To a solution of intermediate (d) (40.7 g withexcess TFA, about 26 mmol) in DCM (200 mL) in the presence of DIPEA (150mL) in ice bath was added diethyl chlorophosphate (6.7 g, 1.5 eq.) inDCM (20 mL) over 4 h via a syringe pump. After the reaction was completeas monitored by HPLC, the reaction mixture was concentrated, thendiluted with EtOAc (200 mL), washed with NaHCO₃ (50 mL×2), H₂O (40mL×4), brine (50 mL×2), and evaporated and purified by flashchromatography (0%-5% MeOH/DCM) to afford compound 2 (6.56 g) (yield:41.8% over 3 steps).

Synthesis of compound 2 salt: a solution of compound 2 (8.41 g) in DCM(100 mL) was stirred at 0° C., then methanesulfonic acid (1.32 g, 1.0eq.) in DCM (10.0 mL) was added slowly. EtOAc (100 mL) was added to theabove mixture very slowly followed by heptane (400 mL). The resultingsuspension was stirred for 2 h, filtered, washed with heptane (30.0mL×3) to give yellow solid. This yellow solid was dried under highvacuum, then dissolved in H₂O (50 mL), freeze drying to furnish compound2 salt (9.40 g). FIG. 3 illustrates the ¹HNMR spectra of compound 2salt, and FIG. 4 illustrates the MS of compound 2 salt.

Example 3: Synthesis of Compound 5

Synthesis of intermediate (k): a mixture of compound (h) (4.90 g, 29.2mmol) and compound (j) (7.1 g, 29.5 mmol, 1.01 eq.) in ACN (150 mL) wasrefluxed for 12 h to generate a slurry. After the reaction was completeas monitored by HPLC, solvent was evaporated under reduced pressure atroom temperature. Then EtOAc (200 mL) and H₂O (60.0 mL) were added tothe reaction mixture. The organic layer was washed with H₂O (40.0 mL×2),brine (30.0 mL), dried over MgSO₄, evaporated and purified by flashchromatography (5%-10% EtOAc/heptane) to afford compound (k) (10.5 g) in96.7% yield.

Synthesis of intermediate (m): to a solution of intermediate (k) (17.2g) in methanol (150 mL) was added NaOH (80.0 mL, 1.0 N) at roomtemperature. The resulting mixture was refluxed at 60° C. for 3 h. Afterthe reaction was complete as monitored by TLC, the reaction mixture wasevaporated under reduced pressure at room temperature and neutralizedwith HCl (2.0 N) to pH 5-6. The mixture was extracted with EtOAc (50.0mL×4). The combined organic layer was washed with brine, dried overMgSO₄, and concentrated in vacuo, affording (m) as a solid (9.9 g,98.0%). The material was used in the next step without furtherpurification.

Synthesis of compound 5: a mixture of compound (m) (3.59 g, 11.0 mmol)and CDI (2.33 g, 14.3 mmol, 1.30 eq.) in THF (40.0 mL) was stirred at30-40° C. for 2 h. Compound (m) (2.38 g, 16.5 mmol, 1.5 eq.) in THF (15mL) was added to the mixture at room temperature slowly. The resultingmixture was stirred at room temperature overnight to give a clearyellowish solution. After the reaction was complete as monitored byHPLC, solvent was evaporated under reduced pressure. Then DCM (100 mL)and H₂O (30.0 mL) were added to the reaction mixture. The aqueous layerwas extracted with DCM (40.0 mL×3). The combined organic layer waswashed with H₂O (40.0 mL×3), brine (30.0 mL), dried over MgSO₄,evaporated and purified by flash chromatography (0%-15% MeOH/DCM) toafford compound 5 (4.95 g) in 92.7% yield.

Synthesis of compound 5 salt: to a solution of compound 5 (7.40 g, 15.3mmol) in EtOAc (25.0 mL) at 0° C. was added phosphoric acid (1.05 mL,1.0 eq.) in EtOAc (10.0 mL) slowly. Heptanes (500 mL) were added to theabove mixture very slowly. The resulting suspension was stirred for 2 h,filtered, washed with heptanes (30.0 mL×3) to afford a white solid. Thesolid was dried under high vacuum, dissolved in H₂O (80 mL), and thenfreeze dried to furnish compound 5 phosphate salt as an off-white gummysolid (9.2 g). FIG. 5 illustrates the ¹HNMR spectra of compound 5 salt,and FIG. 6 illustrates the MS of compound 5 salt.

Example 4: Synthesis of Compound 6

Synthesis of compound (q): to a mixture of intermediate (m) (5.00 g,13.95 mmol) and HOBt (1.89 g, 13.95 mmol, 1.0 eq.) in THF (60.0 mL) inan ice bath was added DCC (3.45 g, 16.74 mmol, 1.2 eq.). The resultingslurry was stirred at room temperature for 2 h. Compound (p) (3.15 g,16.74 mmol, 1.2 eq.) in THF (30.0 mL) was added to this slurry. Thereaction mixture was stirred at room temperature overnight,concentrated, then diluted with EtOAc (200 mL), filtered, washed withEtOAc (20 mL×3). The combined organic layer was treated with NaHCO₃(40.0 mL), NaOH (40 mL, 2.0 N), brine (40 mL×2), dried over MgSO₄,evaporated, and purified by flash chromatography (0%-30% EtOAc/heptane)to afford compound (q) (6.51 g, 88.2%).

Synthesis of compound (r): a suspension of compound (q) (3.86 g, 7.3mmol), NaOtBu (6.92 g, 72.0 mmol, 10 eq.), H₂O (0.17 mL, 1.0 eq.) in2-MeTHF (800 mL) was heated to refluxed for 15 h. After the reaction wascomplete, the mixture was cooled in an ice bath, quenched with saturatedammonium chloride (50.0 mL) to adjust pH to 10-11. The aqueous layer wasextracted with EtOAc (40.0 mL×4), washed with H₂O (40.0 mL×2), brine(30.0 mL), dried over MgSO₄, evaporated, and purified by flashchromatography (5%-50% MeOH/DCM) to afford compound (r) (2.64 g) in84.3% yield.

Synthesis of compound 6: to a solution of compound (r) (4.73 g, 11.04mmol), DIPEA (5.80 mL, 3 eq.) in DCM (80 mL) was added compound (t)(1.92 mL, 1.2 eq.) in an ice bath. The resulting mixture was stirred atroom temperature for 2 h. The mixture was evaporated, diluted with EtOAc(150 mL), washed with NaHCO₃ (40.0 mL), H₂O (40.0 mL×3), brine (30.0mL), dried over MgSO₄, evaporated, purified by different solvent systems(0%-5% MeOH/DCM) and (50%-100% EtOAc/heptane) to give product 6 (5.05 g)as a light yellow oil in 83.7% yield. FIG. 7 illustrates the ¹HNMRspectra of compound 6, and FIG. 8 illustrates the MS of compound 6.

Example 5: Synthesis of Compound 7

Step-1: Synthesis of tert-butyl(2-(4-(2-propylpentanoyl)piperazin-1-yl)ethyl)carbamate (7b): To astirred solution of Compound 7a (22.0 g, 15.22 mmol, 1.0 eq.) in THF(170 mL) was added CDI (28.5 g, 17.56 mmol, 1.0 eq.) at rt. The reactionmixture was stirred at room temperature for 2 h. After 2 h, Compound 7d(45.0 g, 19.86 mmol, 1.3 eq.) in THF (170 mL) was added drop wise to thereaction mixture. After addition was complete the reaction mixture wasstirred at rt for 18 h (The reaction mixture was monitored by TLC).After completion of reaction, the reaction mixture was concentratedunder reduced pressure to get residue. The residue was suspended withwater (300 mL) and extracted with EtOAc (2×400 mL). The combined organiclayer was dried over sodium sulfate and filtered. The solvent wasconcentrated under reduced pressure to get the crude. The crude waspurified through basic silica gel column chromatography using Ethylacetate: Hexane (30:70) as an eluent to get Compound-7b (34.0 g) as apale-yellow color liquid. ¹H-NMR (400 MHz, CDCl₃): δ 5.01 (bs, 0.8H),3.67 (t, J=9.6 Hz, 2H), 3.56 (t, J=9.6 Hz, 2H), 3.24 (t, J=5.2 Hz, 2H),2.66-2.52 (m, 1H), 2.49-2.40 (m, 6H), 1.65-1.62 (m, 2H), 1.47 (s, 9H),1.41-1.34 (m, 3H), 1.30-1.20 (m, 4H), 0.88 (t, J=7.2 Hz, 6H).

Step-2: Synthesis of1-(4-(2-aminoethyl)piperazin-1-yl)-2-propylpentan-1-one (7c): To astirred solution of Compound 7b (32.0 g, 90.14 mmol, 1.0 eq.) in DCM(425 mL) was added TFA (71.9 mL, 63.09 mmol, 7.0 eq.) drop wise at 0° C.for 10 min. The reaction mixture was stirred at rt for 2.5 h. After 2.5h, the reaction mixture was concentrated under reduced pressure to getresidue. The obtained residue was co-distilled with toluene (2×60 mL).The obtained reside was washed with Di Ethyl Ether and dried undervacuum to get Compound-7c. TFA salt. Which was dissolved in mixture ofdichloromethane:water (9:1) and NaHCO₃ (64 g, 2 gram equiv.) was addedand stirred for 30 min. After 30 min, the reaction mixture was filtered,solvent was dried over Na₂SO₄ and filtered The solvent was concentratedunder reduced pressure to get the get Compound-7c (32.0 g) as acolorless liquid. ¹H-NMR (400 MHz, CD₃OD): δ 3.90-3.80 (m, 4H),3.37-3.33 (m, 2H), 3.32-3.30 (m, 2H), 3.28-3.10 (m, 4H), 2.87-2.83 (m,1H), 1.62-1.53 (m, 2H), 1.45-1.38 (m, 2H), 1.37-1.17 (m, 4H), 0.90 (t,J=7.2 Hz, 6H).

Step-3: Synthesis of diethyl(2-(4-(2-propylpentanoyl)piperazin-1-yl)ethyl)-phosphoramidate (Compound7): To a stirred solution of Compound 7c (12.0 g, 47.05 mmol, 1.0 eq.)in DCM (384 mL) was added DIPEA (18.25 g, 14.11 mmol, 3.0 eq.) at rtover a period of 20 min. After 20 min, the reaction mixture was cooledat 0° C., diethyl chlorophosphate (9.97 g, 56.47 mmol, 1.0 eq.) wasadded drop wise over a period of 10 min at 0° C. The reaction mixturewas stirred at rt for 4 h. Reaction was monitored by TLC. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure to get the residue. The residue was dissolved in EtOAc(800 mL) and extracted with saturated NaHCO₃ solution (2×250 mL). Theorganic layer was dried over sodium sulfate and filtered. The solventwas concentrated under reduced pressure to get the crude. The crude waspurified by basic silica gel column chromatography using MeOH: DCM(2:98) as an eluent to get the compound 7 (6.0 g) as a light brown colorliquid in pure form. ¹H-NMR (400 MHz, CDCl₃): δ 4.10-4.05 (m, 4H),3.67-3.55 (m, 2H), 3.40 (bs, 1H), 3.04-2.91 (m, 2H,), 2.54-2.52 (m, 1H),2.50-2.43 (m, 6H), 1.65-1.63 (m, 2H), 1.41-1.29 (m, 9H), 1.28-1.21 (m,4H), 0.88 (t, J=7.2 Hz, 6H). ³¹P-NMR (161.9 MHz, CDCl₃): δ 9.16

Example 6: Cancer Growth Inhibition

Exemplary compounds inhibit the growth of cancer. The therapeuticefficacy of compounds 2, 5, and 6 was assessed in human and murine celllines of varied tissue origin, and their 24 hr 50% inhibitoryconcentration was determined by following standard methodologies.Typical results are shown in the Table 5, indicating a broad anticancereffect.

TABLE 5 24 hr IC₅₀ (μM) SKOV-3 HCT116 RAW264 AGS A549 ovarian colonmurine gastric lung Compound cancer cancer macrophage cancer cancer 2480 460 160 306 400 5 9 10 5 14 19 6 26 7 6 15 31

Ovarian cancer cells were studied in greater detail using the followingovarian cancer cell lines: SKOV-3, OVCAR3, A2780 (and two cell linesderived from it, A2870cis that is resistant to cisplatin, and A2870ADRthat is resistant to doxorubicin (Adriamycin)), and HEY (sensitive topaclitaxel (Taxol), and its derivative HEY-T30 that is Taxol-resistant).Compounds 5 and 6 potently inhibited the growth of these cancer celllines. Table 6 summarizes the results obtained with compound 6. Similarresults were obtained with compound 5.

TABLE 6 24-h IC₅₀ μM Cell line mean ± SEM SKOV-3 26.0 ± 3.2 OVCAR3 22.0± 1.8 A2780 20.3 ± 1.4 A2780cis 20.5 ± 1.1 platinum resistant A2780ADR21.3 ± 0.8 Adriamycin resistant HEY 25.3 ± 0.3 Taxol sensitive HEY T3024.6 ± 0.8 Taxol resistant

Example 7: In Vivo Cancer Growth Inhibition

The ability of compound 5 to inhibit the growth of human ovarian cancercell xenografts in nude mice was determined. A mouse model thatrecapitulates the features of peritoneal spread was used, the peritonealspread being the clinically most relevant presentation of ovariancancer. In this model, luciferase-expressing ovarian cancer cells areinjected intraperitoneally (ip) into nude mice. Multiple tumors grow inthe peritoneal cavity and their growth is monitored periodically usingthe IVIS Lumina II imaging system following the intraperitonealadministration of luciferin, the substrate of luciferase. The luciferasegene was transfected into SKOV-3 cells, and 2×10⁶ cells wereintraperitoneally injected into mice. Two weeks later, when tumors hadgrown, mice treatment was started by intraperitoneally injectingcompound 5, 15 mg/kg or vehicle (corn oil), once a day, six days a week(n=10 mice/group).

As shown in FIG. 9, compound 5 profoundly inhibited the growth of the iptumors. On day 24, compound 5 reduced tumor volume by 153% compared tocontrol (p<0.001). When the tumor volume of the compound 5 treated miceat the end of the study is compared to that of the day when treatmentstarted (baseline), compound 5 caused 53% tumor regression, with 3 outof 10 mice having barely detectable tumors by imaging and no tumorsvisible at necropsy. Compound 6 produced virtually identical results.

Compound 6 administered to the same animal model at the dose of 100mg/kg once a day, six days a week, produced virtually identical resultswith compound 5. Compound 6 was also efficacious againstchemotherapy-resistant ovarian cancer. This was demonstrated in humanovarian cancer cell-line subcutaneous xenografts in nude mice. Theeffect of compound 6 in cisplatin resistant (A2780cis) and doxorubicin(Adriamycin) resistant (A2780ADR) tumors was studied. Briefly, each ofthese cell lines was subcutaneously inoculated into athymic nude miceand when the tumor size reached 100-200 mm³, compound 6 150 mg/kg/day orits vehicle were given i.p. After 11 days of treatment, for thecisplatin-resistant tumors the tumor volume of the vehicle group was2388±127 mm³ and for compound 6 group 1032±108 mm³ (mean±SEM; P<0.02);while for the doxorubicin-resistant tumors these values were: vehiclegroup=1369±337 mm³ and compound 6 group=396±182 mm³ (P<0.02).

Example 8: In Vivo Efficacy Against Chemotherapy-Resistant OvarianCancer

To determine whether compound 5 is efficacious againstchemotherapy-resistant ovarian cancer, three pairs of sensitive andresistant human ovarian cancer cell lines were grown as subcutaneousxenografts in nude mice and treated as summarized in FIG. 10. These celllines were: A2780, sensitive to both cis-platinum and Adriamycin(doxorubicin); A2780cis, resistant to cis-platinum; A2780ADR, resistantto Adriamycin: HEY, sensitive to Taxol; HEY-T30, resistant to Taxol.When tumor volume was about 150 mm³, mice were treated as indicated inthe figure. The treatments administered were: vehicle control; compound5, 15 mg/kg/day six days a week, ip; cis-platinum 5.5 mg/kg, one time aweek ip; Adriamycin 3 mg/kg twice a week ip; and Taxol 20 mg/kg twice aweek ip. As shown in FIG. 10, compound 5 and cis-platinum suppressed thegrowth of the platinum-sensitive xenografts with equal efficacy. In theplatinum-resistant xenografts, compound 5 was as efficacious as in theplatinum sensitive xenografts, whereas platinum failed to significantlyinhibit tumor growth. The same pattern of response was observed forcompound 5 vs. Adriamycin, and compound 5 vs. Taxol. These results,consistent with the in vitro data, demonstrate the ability of compound 5to overcome drug resistance in ovarian cancer, a critical determinant ofthe clinical outcome in this often lethal malignancy.

Example 9. The Mechanism of the Anticancer Effects of Compounds 5 and 6

Further studies devaluated the mechanism of action of exemplarycompounds 5 and 6, demonstrating that they are distinct from each otherand also from other known compounds.

The dominant mechanistic effect of compound 5 is the induction of theintegrated stress response (ISR) and endoplasmic reticulum stress (ERS).These stresses are of such magnitude that they exceed the pro-survivalthreshold, triggering cell death through autophagy and apoptosis, atherapeutically useful outcome. Normal cells are spared this effect.This mechanism of action operates in both sensitive and resistant cellsand may explain the ability of compound 5 to overcome resistance tochemotherapy. This mechanism is summarized in FIG. 11, while FIGS.12A-12C and 13A-13C illustrate the key findings that support thismechanism.

Compound 6 has an entirely different mechanism of action, basedpredominantly on the induction of a different type of stress in ovariancancer cells, namely oxidative stress. Oxidative stress, depending onits degree, can induce cancer cell death, mainly through apoptosis, thusmediating the effect of anticancer agents. This mechanism is summarizedin FIG. 14, FIG. 15, and FIG. 16, which illustrate the key findings thatsupport this mechanism.

Example 10. Synergy with Chemotherapeutic Agents

It was further demonstrated that at low doses an exemplary compound 5synergizes with low doses of cyclophosphamide to inhibit the growth ofchemotherapy-resistant ovarian cancer. As shown in FIG. 17, subcutaneousxenografts in nude mice of the Taxol resistant human ovarian cancer cellline HEY-T30 were treated with vehicle control or compound 5 10mg/kg/day six days a week ip, or cyclophosphamide 10 mg/kg six days aweek orally or both of them at the same doses. Compared to control,neither agent alone produced significant imbibition of tumor growth.Their combination, however, not only inhibited significantly tumorgrowth (58% on day 21), but its magnitude established synergy as itexceeded the sum of each drug alone (26% and 23%, respectively, on day21).

Furthermore, in vitro studies using cultured human cancer cells revealedthe synergistic action of exemplary compounds with various anticanceragents. For example, compound 5 synergizes with tamoxifen to essentiallyeliminate (when tamoxifen is administered prior to compound 5) orsignificantly reduce (if given concurrently with, or prior to,tamoxifen) the growth of MIA PaCa2 human pancreatic cancer cells.Additionally, synergy has been documented between compounds 5 and 6individually and several chemotherapeutic and other agents, includingbut not limited to various camptothecins (e.g., camptothecin 11),resveratrol, gemcitabine, docetaxel, curcumin, progesterone, andmethotrexate. Such synergy concerned the ability of these combinationsto markedly suppress the growth of various human cancer cell linesoriginating in the pancreas, lung and other tissues. Furthermore,extremely efficacious was the combination of compounds 5, 6 andtamoxifen in completely suppressing the growth of K-ras mutant humanpancreatic cancer cell lines.

Example 11: Exemplary Compounds Inhibit VEGF Expression

Pathological angiogenesis is a hallmark of cancer. Tumor growth andmetastasis rely heavily on development of new blood vessels. Thevascular endothelial growth factor (VEGF) is the most prominent moleculeinvolved in vascular growth. VEGF promotes the formation of tumor bloodvessels, and tumors cannot grow beyond a critical size without adequateblood supply. Pathological angiogenesis is also important in diabeticretinopathy, a common cause of blindness. VEGF plays a critical role inthe diabetic retinopathy and is a therapeutic target.

The effect of compounds 2, 5, and 6 on VEGF production was examined. Forexample, SKOV-3 ovarian cancer cells grown in culture were treated withcompound 5 l×IC₅₀ for up to 24 h. Secreted VEGF was assayed in theculture medium by ELISA (R&D Systems). Compound 5 time-dependentlysuppressed VEGF-A levels, reaching 80% by 6 hr and 100% at 24 hr.Similar results were obtained with additional ovarian cancer cell lines.For example, at 24 h, the reduction of secreted VEGF-A over thecorresponding controls was: OVCAR3=100%, A2780=86%, A2780cis=100%, andA2780ADR=100%. Compound 5 suppressed VEGF-B by 90-92% compared tocontrol. The anti-VEFG effect of Compound 5 is as strong in thedrug-resistant as in the drug-sensitive cell lines. Compound 6 gavesimilar results.

Example 12: Exemplary Compounds Inhibit the Activation of Mutant K-Ras

An unexpected property of the compounds of the invention is that theystrongly inhibit the activation of mutant K-Ras. This effect may beparticularly useful in types of cancer characterized by K-Ras mutationsuch as, for example, pancreatic, lung and ovarian cancer. FIG. 18Aillustrates the inhibition of K-Ras activation by compound 6. Notablyand unexpectedly, exemplary compound 5 suppressed the activation ofmutant K-Ras not by the mechanism by which compound 6 inhibited it, butby suppressing its palmitoylation (FIG. 18B), a lipid modification thatis required for Ras action in driving cancer. This property of compound5 is not shared for example by compound 6 or phosphosulindac.

Example 13: Exemplary Compounds Reach the Posterior Chamber of the Eye

Biodistribution of the compounds of Formula A-D-Y is determined aftertopical administration as in vivo eye drops to the eyes of New Zealandwhite rabbits. Biodistribution of the compound of Formula A-D-Y can alsobe determined after topical administration to human cadaveric eyes,preserved on ice and used within 2 h from removal from the donors. Theanterior surface of the human eye (corresponding to an area slightlylarger than the palpebral fissure) is brought into direct contact with aformulation of the invention and incubated for about 10 min at 37° C.The eye is then rinsed with 10% dimethylsulfoxide (DMSO) to removeresidual PS from the surface of the eye without damaging ocular tissue,and incubated in PBS for 60 min. At specific time intervals, oculartissues are dissected and Formula A-D-Y compounds levels determined byHPLC.

The pharmacokinetics and biodistribution of compounds 1, 2, and 5 in theeye of rabbits were determined. Each of these compounds was dissolved inphosphate buffered saline (PBS) and used as eye drops. The eye dropswere sterilized before application to rabbits by filtration through a0.2 μm membrane. New Zealand rabbits were each administered three 25 μleye drops, one drop every 5 min, and euthanatized 1 or 3 h later. Theeyes were harvested and eye tissues and the lacrimal glands weredissected, homogenized and the test compounds were extracted byacetonitrile and analyzed by HPLC, as described under Compound Synthesisdescribed herein. Compounds 1 and 2 were detected at 328 nm, andcompound 5 at 260 nm. Table 7 shows the results obtained. All threecompounds can unexpectedly, readily, and rapidly reach the posteriorchamber of the eye.

TABLE 7 Drug levels in rabbit ocular tissues Compound 1 Compound 2Compound 5 20% 20% 20% Tissue 1 hr 3 hr 2 hr 3 hr 40 min 60 min Cornea61.8 16.2 106.1 46.0 75.7 96.7 Conjunctiva 71.6 52.5 16.1 13.5 33.2 35.1Sclera 10.1 2.5 50.7 22.4 1.3 0.6 Iris 6.9 7.6 9.9 9.8 0.6 1.9 Lens 20.24.6 0.3 4.0 0.0 0.0 Aqueous humor 1.5 0.8 8.2 2.0 0.0 0.0 Vitreous 0.90.5 1.2 NA 0.0 0.0 Retina 7.5 1.8 4.1 1.7 1.8 3.4 Ciliary body ND ND NDND 0.0 4.2 Choroid 4.1 2.1 5.3 6.4 NA NA Lacrimal gland 2.2 0.2 ND ND0.0 0.0 ND: Not Detectable; NA: Not Assayed

Ocular PK/biodistribution studies in rats using another exemplarycompound, compound 6, demonstrated the following. Compound 6 3%(formulated in polyethylene glygol 155; Tween 80% 1%; Kolliphor EL 10%,made to 100% with normal saline; pH 7.2) was injected iv as a singledose of 30 mg/kg. Its retina levels were 4.9 μM and 1 μM at 1 h and 2 h,respectively (the corresponding sclera levels were similar, 3.2 μM and2.0 μM). When compound 6 was given ip (in corn oil) as a single dose of100 mg/kg its retina levels became detectable at 3 h (3.2 μM) andremained at 2.8 μM at 4 h and 6 h. Similarly, after its single topicaladministration, compound 6 3% (formulated in vitamin E TPGS 16%,mannitol 3.2% boric acid 1.2% and polyquad 0.005%, pH 7.2) producedretinal levels of 2.1 μM at 4 h. The biodistribution of compound 2 inhuman eyes that were recently removed from deceased donors and kept onice until used within hours was also evaluated. In this study, compound2 was dissolved in pure water; its pH was adjusted to 4.8±0.1 and itsosmolarity to 290 mOsm. The final concentration of compound 2 was 10%(w/v).

The anterior surface of each was brought into contact with the abovesolution of compound 2 at 37° C.; the solution level was about 3 mmabove the cornea edge. After 1 minute or 10 minutes the eyes were rinsedthoroughly with PBS, incubated for 1 h, and dissected to harvest theretina, choroid, aqueous humor, ciliary body, iris and cornea, which ereassayed by HPLC. As shown in the below table, compound 2 did reach theposterior segment of the eye.

Compound 2, μM Tissue 1 minute exposure 10 minutes exposure retina 12.646.6 choroid 425.9 273.5 aqueous humor 1.0 5.3 ciliary body 124.6 206.9iris 43.1 10.3 cornea 166.3 512.6

Example 14: Exemplary Compounds Inhibit Oxygen Induced Retinopathy InVivo

Several animal models have been explored to understand retinal vasculardevelopment. The mouse model of oxygen-induced retinopathy is the mostwidely used, and has played a pivotal role in our understanding ofretinal angiogenesis and in the development of therapeutics such asanti-vascular endothelial growth factor injections for wet age-relatedmacular degeneration. In this model, retinas possess extensive centralvaso-obliteration with pathologic neovessels forming around the junctionof the vascular and avascular zones, mirroring oxygen-inducedretinopathy in humans.

C57BL/6 mice were reared in 75±2% oxygen air starting on postnatal day 7(P7) and moved into room air on P12, when they were injectedintravitreally with 1 μl of 1% compound 6 solution or vehicle. On P17,the pups were euthanized, both eyes were enucleated and fixed with 4%paraformaldehyde (PFA). Following several intermediate steps, the retinawas existed and fixed further with 4% PFA overnight. After appropriatewashings, the retina was incubated with 10 μg/ml of FITC-conjugatedanti-lectin antibody overnight and retina flat-mounts were prepared onglass slides and evaluated by fluorescence microscopy. The areas of theavascular, neovascular and whole retina were determined using ImageJsoftware.

As shown in FIG. 19, compared to vehicle-treated controls, treatment ofthese mice with compound 6, dramatically reduced the central avasculararea (75% inhibition; p<0.001) as well as the peripheralneovascularization (51% inhibition; p<0.04), returning retinalvasculature towards normal.

Consistent with these findings is the ability of compound 6 to inhibitvessel formation in vitro (FIG. 20) using a) the tube formation assay(it models the reorganization stage of angiogenesis) by cultured humanvascular endothelial cells (HUVEC) in which these two compounds markedlysuppressed the formation of capillary-like structures. (a.k.a. tubes),with for example compound 6 30 μM suppressing branch points by 97%(p<0.001); and b) The chicken embryo chorioallantoic membrane assay, anestablished model for studying neovascularization, in which compound 5reduced the formation of new vessels by 21% (58±4.9 to 46±2.1; p<0.04)and compound 6 reduced it by 37% (42.6±8.2 to 27±1.5; p<0.03).

In another study, the same mouse model of oxygen-induced retinopathydescribed above was used. In this study, mice were treated daily with anaqueous solution of compound 2 (pH=4.6, osmolarity=282 mOsm;concentration=10% w/v) from postnatal day 12 to day 17. Compound 2 wasadministered as one eye drop per eye every 2 hours during the day timefor a total of 5 administrations daily. At the end of the study, micewere euthanized and their retinas dissected and studied byimmunofluorescence using an antibody against lectin I, isolectin B4(Vector Laboratories) and evaluated as above.

FIG. 21 demonstrates that compound 2 had a major effect on retinopathy.Specifically, compound 2 significantly reduced the avascular area(vehicle=16.8±1.1 vs. compound 2=5.8±0.8; p<0.0001) and also theneovascular area (vehicle=20.7±3.7 vs. compound 2=9.9±2.2; p<0.029) ofthe retina. n=8 group.

A number of patent and non-patent publications are cited herein in orderto describe the state of the art to which this invention pertains. Theentire disclosure of each of these publications is incorporated byreference herein.

While certain embodiments of the present invention have been describedand/or exemplified above, various other embodiments will be apparent tothose skilled in the art from the foregoing disclosure. The presentinvention is, therefore, not limited to the particular embodimentsdescribed and/or exemplified, but is capable of considerable variationand modification without departure from the scope and spirit of theappended claims.

REFERENCES

-   1. Prager G W, Braga S, Bystricky B, Qvortrup C, Criscitiello C,    Esin E, et al. Global cancer control: responding to the growing    burden, rising costs and inequalities in access. ESMO Open 2018;    3(2):e000285.-   2. Global Burden of Disease Cancer C, Fitzmaurice C, Akinyemiju T F,    Al Lami F H, Alam T, Alizadeh-Navaei R, et al. Global, Regional, and    National Cancer Incidence, Mortality, Years of Life Lost, Years    Lived With Disability, and Disability-Adjusted Life-Years for 29    Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global    Burden of Disease Study. JAMA Oncol 2018.-   3. Fidler M M, Bray F, Soerjomataram I. The global cancer burden and    human development: A review. Scand J Public Health 2018;    46(1):27-36.-   4. Nikolaou M, Pavlopoulou A, Georgakilas A G, Kyrodimos E. The    challenge of drug resistance in cancer treatment: a current    overview. Clin Exp Metastasis 2018; 35(4):309-18.-   5. Reid B M, Permuth J B, Sellers T A. Epidemiology of ovarian    cancer: a review. Cancer Biol Med 2017; 14(1):9-32.-   6. Cortez A J, Tudrej P, Kujawa K A, Lisowska K M. Advances in    ovarian cancer therapy. Cancer Chemother Pharmacol 2018;    81(1):17-38.-   7. Giornelli G H. Management of relapsed ovarian cancer: a review.    Springerplus 2016; 5(1):1197.-   8. Doubeni C A, Doubeni A R, Myers A E. Diagnosis and Management of    Ovarian Cancer. Am Fam Physician 2016; 93(11):937-44.-   9. Matulonis U A, Sood A K, Fallowfield L, Howitt B E, Sehouli J,    Karlan B Y. Ovarian cancer. Nat Rev Dis Primers 2016; 2:16061.-   10. Duh E J, Sun J K, Stitt A W. Diabetic retinopathy: current    understanding, mechanisms, and treatment strategies. JCI Insight    2017; 2(14).-   11. National Institutes of Health. National Cancer Institute.    Surveillance, Epidemiology, and End Results Program. Statistical    summaries: cancer stat fact sheets (ovary) and cancer statistics    review (CSR), 1975-2013,    http://seer.cancer.gov/statistics/summaries.html, 2016.-   12. Rosen D G, Yang G, Liu G, Mercado-Uribe I, Chang B, Xiao X S, et    al. Ovarian cancer: pathology, biology, and disease models. Front    Biosci (Landmark Ed) 2009; 14:2089-102.-   13. Itamochi H. Targeted therapies in epithelial ovarian cancer:    Molecular mechanisms of action. World J Biol Chem 2010; 1(7):209-20.-   14. Coward J I, Middleton K, Murphy F. New perspectives on targeted    therapy in ovarian cancer. Int J Womens Health 2015; 7:189-203.-   15. Westin S N, Herzog T J, Coleman R L. Investigational agents in    development for the treatment of ovarian cancer. Invest New Drugs    2013; 31(1):213-29.-   16. Markman M, Walker J L. Intraperitoneal chemotherapy of ovarian    cancer: a review, with a focus on practical aspects of treatment. J    Clin Oncol 2006; 24(6):988-94.-   17. Narod S. Can advanced-stage ovarian cancer be cured? Nat Rev    Clin Oncol 2016; 13(4):255-61.-   18. Coleman R L, Monk B J, Sood A K, Herzog T J. Latest research and    treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin    Oncol 2013; 10(4):211-24.-   19. Romero I, Bast R C, Jr. Minireview: human ovarian cancer:    biology, current management, and paths to personalizing therapy.    Endocrinology 2012; 153(4):1593-602.-   20. Vaughan S, Coward J I, Bast R C, Jr., Berchuck A, Berek J S,    Brenton J D, et al. Rethinking ovarian cancer: recommendations for    improving outcomes. Nat Rev Cancer 2011; 11(10):719-25.-   21. Bowtell D D, Bohm S, Ahmed A A, Aspuria P J, Bast R C, Jr.,    Beral V, et al. Rethinking ovarian cancer II: reducing mortality    from high-grade serous ovarian cancer. Nat Rev Cancer 2015;    15(11):668-79.-   22. Cheng K W, Wong C C, Alston N, Mackenzie G G, Huang L, Ouyang N,    et al. Aerosol administration of phospho-sulindac inhibits lung    tumorigenesis. Mol Cancer Ther 2013; 12(8): 1417-28.-   23. Mackenzie G G, Sun Y, Huang L, Xie G, Ouyang N, Gupta R C, et    al. Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe    and effective in colon cancer prevention in mice. Gastroenterology    2010; 139(4):1320-32.-   24. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman    A M. The integrated stress response. EMBO Rep 2016; 17(10):1374-95.-   25. Oakes S A, Papa F R. The role of endoplasmic reticulum stress in    human pathology. Annu Rev Pathol 2015; 10:173-94.-   26. Rigas B, Sun Y. Induction of oxidative stress as a mechanism of    action of chemopreventive agents against cancer. Br J Cancer 2008;    98(7):1157-60.-   27. Sun Y, Huang L, Mackenzie G G, Rigas B. Oxidative stress    mediates through apoptosis the anticancer effect of    phospho-nonsteroidal anti-inflammatory drugs: implications for the    role of oxidative stress in the action of anticancer agents. J    Pharmacol Exp Ther 2011; 338(3):775-83.-   28. Yokoyama C, Sueyoshi Y, Ema M, Mori Y, Takaishi K, Hisatomi H.    Induction of oxidative stress by anticancer drugs in the presence    and absence of cells. Oncol Lett 2017; 14(5):6066-70.-   29. Lin DTS, Davis N G, Conibear E. Targeting the Ras    palmitoylation/depalmitoylation cycle in cancer. Biochem Soc Trans    2017; 45(4):913-21.-   30. Olivares A M, Althoff K, Chen G F, Wu S, Morrisson M A,    DeAngelis M M, et al. Animal Models of Diabetic Retinopathy. Curr    Diab Rep 2017; 17(10):93.-   31. Kim C B, D'Amore P A, Connor K M. Revisiting the mouse model of    oxygen-induced retinopathy. Eye Brain 2016; 8:67-79.

1. A compound of Formula A-D-Y, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selectedfrom the group consisting of A¹ to A⁴⁰ as defined in Table
 1. 2. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, wherein D is selected from thegroup consisting of D¹ to D⁷ as defined in Table
 2. 3. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, hydrate,cocrystal, or prodrug thereof, wherein Y is selected from the groupconsisting of Y¹ to Y⁷ as defined in Table
 3. 4. The compound of claim3, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal,or prodrug thereof, wherein D is selected from the group consisting ofD¹ to D⁷ as defined in Table
 2. 5. The compound of claim 1, wherein thecompound is selected from the group consisting of compound 1, compound2, compound 3, compound 4, compound 5, compound 6, and compound 7, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof:


6. The compound of claim 1, wherein the compound has anti-inflammatory,anticancer, or antiangiogenic effects.
 7. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable salt,solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceuticallyacceptable excipient.
 8. A method of treating a disease or disorder in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof.
 9. The method of claim 8, wherein the compound, or thepharmaceutically acceptable salt, solvate, hydrate, cocrystal, orprodrug thereof, is included in a pharmaceutical composition furthercomprising a pharmaceutically acceptable excipient.
 10. The method ofclaim 8, wherein the disease or disorder is an inflammation disease ordisorder, a cancer, a neurodegenerative disease or disorder, acardiovascular disease or disorder, an ocular disease or disorder, or anangiogenic disease or disorder.
 11. The method of claim 10, wherein thecancer is ovarian cancer, colon cancer, leukemia, gastric cancer, lungcancer, pancreatic cancer, or a cancer characterized by one or moreK-Ras mutations.
 12. The method of claim 10, wherein the cancer ischemoresistant to one or more other therapeutic agents.
 13. (canceled)14. The method of claim 8, wherein the disease or disorder is an oculardisease or disorder.
 15. The method of claim 10, wherein the oculardisease or disorder is diabetic retinopathy.
 16. The method of claim 10,wherein the ocular disease or disorder is dry eye disease.
 17. Themethod of claim 10, wherein the ocular disease or disorder is aretinopathy selected from the group consisting of diabetic retinopathy,retinopathy of prematurity, VEGF retinopathy, age related maculardegeneration, retinal vein occlusion, and hypertensive retinopathy. 18.The method of claim 8, further comprising administering atherapeutically effective amount of an additional active agent.
 19. Themethod of claim 18, wherein the additional active agent is selected fromthe group consisting of an antibiotic, cyclosporine, lifitegrast, and acombination thereof.
 20. The method of claim 8, wherein the compound isadministered topically to the patient.
 21. The method of claim 20,wherein the compound is administered topically to the patient in an eyedrop dosage form.
 22. The method of claim 8, wherein the compound isadministered by intraocular injection.
 23. The compound of claim 1,wherein the compound, or the pharmaceutically acceptable salt, solvate,hydrate, cocrystal, or prodrug thereof, inhibits VEGF expression.